Synthetic techniques and intermediates for polyhydroxy, dienyl lactones and mimics thereof

ABSTRACT

Synthetic methods for lactone-containing compounds such as the discodermolides are provided, as are compounds which mimic the chemical and/or biological activity thereof, and methods and intermediates useful in their preparation.

GOVERNMENT SUPPORT

Certain of the inventors were supported by National Institutes of HealthGrant GM-29028.

FIELD OF THE INVENTION

This invention relates to lactone-containing compounds such asdiscodermolide, to compounds which mimic the chemical and/or biologicalactivity thereof, and to methods and intermediates useful in theirpreparation.

BACKGROUND OF THE INVENTION

In 1990, Gunasekera and co-workers at the Harbor Branch OceanographicInstitute reported the isolation of (+)-discodermolide (1), anarchitecturally novel metabolite of the marine sponge Discodermiadissoluta (0.002% w/w). (See, Gunasekera, et al., J. Org. Chem. 1990,55, 4912. Correction: J. Org. Chem. 1991, 56, 1346). ##STR1##

Initial studies revealed that (+)-discodermolide suppresses both thetwo-way mixed-lymphocyte reaction and the concanavalin A-inducedmitogenesis of murine splenocytes in vitro with no associatedcytotoxicity. Moreover, (+)-1 suppresses the in vivo graft-vs.-hostsplenomegaly response induced by injection of parental splenocytes intoF1 recipient mice, with potency intermediate between those ofcyclosporin A and FK506. (Longley, et al., Transplantation 1991, 52,650; Longley, et al., Transplantation 1991, 52, 656; Longley, et al.Ann. N.Y. Acad. Sci. 1993, 696, 94). These findings stimulated therecent discovery that (+)-1 arrests cell development at the M phase bybinding and stabilizing mitotic spindle microtubules; thusdiscodermolide resembles taxol in its mode of action, but themicrotubule binding affinity of 1 is much higher. (ter Haar, et al.,Biochemistry 1996, 35, 243; Hung, et al., Chemi. & Biol. 1996, 3, 287).These and other results suggest that (+)-discodermolide holdsconsiderable promise as an anticancer agent. The scarcity of naturalmaterial however has precluded a complete evaluation of its biologicalprofile.

The absolute configuration of discodermolide remained undefined untilSchreiber et al. synthesized both antipodes of 1. (Nerenberg, et al. J.Am. Chem. Soc. 1993, 115, 12621; Hung, et al., Chem. & Biol. 1994, 1,67). Interestingly, the unnatural (-) antipode also displays significantimmunosuppressant activity.

There is, therefore, a need for improved synthetic methods for thepreparation of polyhydroxy, dienyl lactones such as the discodermolides,as well as a need for compounds having similar chemical and/orbiological activity.

OBJECTS OF THE INVENTION

It is one object of the present invention to provide polyhydroxy, dienyllactones and mimics thereof.

It is a further object to provide processes for the preparation of suchcompounds and their mimics.

It is another object of this invention to provide intermediates usefulin such processes.

SUMMARY OF THE INVENTION

These and other objects are satisfied by the present invention, which,in one aspect, provides synthetic methods for the discodermolides andother polyhydroxylactones. In preferred embodiments, such methodsinvolve contacting a phosphonium salt of formula I: ##STR2## with baseand an alkylthiol of formula II: ##STR3## to form a diene of formulaIII: ##STR4## wherein: R₁, R₂, R₃, R₆, R₇, R₈, R₁₁, R₁₂ and R₁₃ are,independently, C₁ -C₁₀ alkyl;

X is a halogen;

Z, Z₁, and Z₂ are, independently, O, S or NR';

R₄, R₉, R₁₄, and R₁₅ are, independently, acid labile hydroxyl protectinggroups;

R₅ is C₆ -C₁₄ aryl;

Y is O, S or NR';

R' and R₁₆ are, independently, hydrogen or C₁ -C₆ alkyl; and

R₁₈ is C₆ -C₁₄ aryl.

In another aspect, the methods of the invention involve producing analkene of formula IV. ##STR5## This can be accomplished by contacting anorganometallic reagent of formula Va: ##STR6## with a vinyl halide offormula VIa: ##STR7## wherein M is Li, Cu, Mg, or Zn and R₁₀ is an acidstable hydroxyl protecting group and all other variables are as definedabove. Alternatively, a vinyl halide of formula Vb: ##STR8## can becontacted with an organometallic compound of formula VIb: ##STR9##

In yet another aspect, the methods of the invention involve lactoneshaving formula VII. ##STR10## by contacting a diene of formula VIIIa:##STR11## with an organometallic compound having formula Va wherein R₂₄is hydrogen and R₂₅ is hydrogen or an acid stable hydroxyl protectinggroup. Alternatively, an organometallic compound having formula VIIIbcan be contacted with a vinyl halide having formula Vb. ##STR12##

The methods of the invention also involve producing dienes havingformula VIIIa by contacting phosphonium salts having formula IX:##STR13## with base and alkylthiol compounds having formula II.

The present invention also provides synthetic intermediates which areuseful in the preparation of polyhydroxylactones, including thecompounds having formulas I-IX and X: ##STR14## wherein: R₁₉, R₂₀, R₂₁and R₂₂ are, independently, C₁ -C₁₀ alkyl; and

R₂₃ is C₇ -C₁₅ aralkyl.

The present invention also provides compounds which mimic the chemicaland/or biological activity of the discodermolides. In preferredembodiments, such compounds have formula XI: ##STR15## where R₃₀ issubstituted or unsubstituted C₁ -C₁₀ alkyl or a moiety formula XII orXIII: ##STR16## where A is C₁ -C₂₀ alkyl, --CH₂ NH(T) or a moiety offormula XIV: ##STR17## wherein T is peptide having 1 to about 10 aminoacids;

R₃₂, R₄₀, R₄₂, R₄₃, R₄₆, R₄₇, and R₄₈ are, independently, hydrogen or C₁-C₆ alkyl;

R₄₁ is a side chain of an amino acid;

W₁ and W₂ are, independently, --OR₄₉ or --NHP₁ ;

P₁ is hydrogen or an amine protecting group;

R₃₃ and R₃₆ are, independently, hydrogen, C₁ -C₁₀ alkyl, --OR₅₀, ═O ortogether form --CH₂ --CH₂ --;

R₃₄ and R₃₅ are, independently, hydrogen or together form--C(H)═C(H)--C(H)═C(H)--;

R₃₉ is --OR₅₁ or --CH₂ --R₅₁ ;

R₃₁ and R₄₄ are, independently, C₁ -C₁₀ alkyl;

Q₁ and Q₂ are, independently, hydrogen, --OR_(Q), --NHR₅₂, --OC(═O)NH₂or together form --O--C(O)--NH--;

R_(Q) is hydrogen or a hydroxyl protecting group;

R₅₁ is substituted or unsubstituted C₆ -C₁₄ aryl, tetrahydropyranyl,furanosyl, pyranosyl (e.g., tetramethylfucosyl, tetramethylmannosyl,tetramethylgaractosyl and tetramethylglucosyl), C₃ -C₁₀ lactonyl or2-pyranonyl;

R₄₅ is C₁ -C₆ alkenyl, C₁ -C₆ alkyl, C₆ -C₁₄ aryl, C₂ -C₁₀heterocycloalkyl, C₃ -C₁₀ cycloalkyl, or C₇ -C₁₅ aralkyl; and

R₄₉, R₅₀, and R₅₂ are, independently, hydrogen or C₁ -C₆ alkyl.

The present invention also provides methods for inhibiting mammaliancell proliferation by contacting mammalian cells with a compoundaccording to the invention or by administering a compound according tothe invention (or a pharmaceutical composition comprising such acompound) to a mammal suffering from undesired cell proliferation. Alsoprovided are methods for inhibiting rejection of a transplanted organ ina mammal comprising administering a compound or composition according tothe invention to a mammalian organ recipient.

BRIEF DESCRIPTION OF THE DRAWINGS

The numerous objects and advantages of the present invention may bebetter understood by those skilled in the art by reference to theaccompanying figures, in which:

FIG. 1 shows a retrosynthetic analysis for (-)-discodermolide 1.

FIG. 2 shows a synthetic scheme for compound 5.

FIG. 3 shows a synthetic scheme for fragment A.

FIG. 4 shows a synthetic scheme for compound 22.

FIG. 5 shows a synthetic scheme for compound 39.

FIG. 6 shows a synthetic scheme for compounds 15 and 25.

FIG. 7 shows a synthetic scheme for compound 34.

FIG. 8 shows a synthetic scheme for fragment C.

FIG. 9 shows a synthetic scheme for fragment B.

FIG. 10 shows a synthetic scheme for compound 39.

FIG. 11 shows a synthetic scheme for compound 40.

FIG. 12 shows a synthetic scheme for compound 49.

FIG. 13 shows a synthetic scheme for compounds 53 and 46.

FIG. 14 shows a synthetic scheme for compound 56.

FIG. 15 shows a synthetic scheme for compound 1.

FIG. 16 shows a synthetic scheme for compound 104.

FIG. 17 shows a synthetic scheme for compound 107.

FIG. 18 shows a synthetic scheme for compound 206.

FIG. 19 shows a synthetic scheme for compound 212.

FIG. 20 shows a synthetic scheme for compound 217.

FIG. 21 shows a synthetic scheme for compound 305.

FIG. 22 shows a synthetic scheme for compound 309.

FIG. 23 shows a synthetic scheme for compound 401.

FIG. 24 shows a synthetic scheme for compound 501.

FIG. 25 shows a synthetic scheme for compound 601.

FIG. 26 shows a synthetic scheme for compound 701 (R=alkyl).

FIG. 27 shows a synthetic scheme for compound 808.

FIG. 28 shows a synthetic scheme for compound 801.

FIG. 29 shows a synthetic scheme for compound 901.

FIG. 30 shows a synthetic scheme for compound 1003.

FIG. 31 shows a synthetic scheme for compound 1104(Ar=2,4-dimethyl-3-methoxyphenyl (a), 2-methyl-5-methoxyphenyl (b),2,4-dimethyl-5-methoxyphenyl (c), 2,4-dimethylphenyl (d), and4-methylphenyl (e)).

FIGS. 33-36 show representative compounds of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

It has been found in accordance with the present invention that thesynthesis of polyhydroxy, dienyl lactones such as the discodermolidescan be achieved by highly convergent and stereocontrolled syntheticprocedures.

As shown in FIG. 1 for the (-)-discodermolide antipode, our analysisrevealed a repeating triad of contiguous stereocenters, separated byZ-olefinic linkages at C(8,9) and C(13,14). Disconnections at C(8,9),C(14,15) and C(21,22) generated fragments A, B and C, each deriving inturn from a common precursor (5) containing the recurring stereochemicaltriad.

As shown in FIG. 2, precursor 5 was prepared by a synthetic procedurewhereby hydroxy ester (-)-6 was protected as the p-methoxybenzyl (PMB)ether by treatment with the Bundle trichloroimidate reagent 7 underacidic conditions. Reduction with LiAlH₄ provided the alcohol (-)-8after distillation.

Swern oxidation, Evans aldol condensation, and Weinreb amide formationcompleted the construction of common precursor (+)-5.

This concise five-step synthesis could be routinely carried out on a50-g scale in 59% overall yield.

In view of the polypropionate structure of the A fragment, we performeda second asymmetric aldol reaction, as shown in FIG. 3. Initialformation of the p-methoxybenzylidene acetal (-)-11 from commonprecursor (+)-5 (78% yield) was designed to allow selective deprotectionof C(21) and C(19) hydroxyls for introduction of the terminal diene andcarbamate moieties. Following reduction of amide (-)-11 to the aldehyde(80% yield), (aldol reaction with oxazolidinone (+)-9 (80% yield)provided alcohol (+)-13 which incorporated the five stereocenters ofsubunit A. The structure of (+)-13 was confirmed by single-crystal X-rayanalysis. Protection of the secondary alcohol as the TBS ether andremoval of the chiral auxiliary (LiBH₄,EtOH,THF) afforded primaryalcohol (-)-15 (81% yield, two steps), which could be efficientlyconverted either to tosylate (-)-16 or iodide (-)-A.

As outlined in FIG. 1, our strategy required a Z vinylic halide B forcoupling with fragment A. Beginning again with the common precursor(+)-5, TBS protection (FIG. 4) followed by reduction of the Weinrebamide DIBAL (2 equiv), THF, -78° C.! (Kim, et al., Tetrahedron Lett.1989, 30, 6697)¹⁶ afforded aldehyde (+)-18 in 88% yield for the twosteps. We adopted a stepwise approach to introduction of the vinylhalide, whereby (+)-18 was converted to the Z α-bromo unsaturated ester(-)-19 (Ph₃ PCBrCO₂ Et, PhH, reflux; 75% yield after chromatography).Reduction to allylic alcohol (-)-20 followed by mesylation anddisplacement with LiBHEt₃ then furnished Z vinyl bromide (-)-22 in 77%overall yield from 19.

Our preferred synthetic strategy involves selective removal of a primaryPMB ether in the presence of a PMP acetal in the AB coupling product((-)-39, FIG. 5). A 1:1 mixture of PMB ether (-)-22 and PMP acetal(-)-15 was exposed to DDQ (1.1 equiv) in CH₂ Cl₂ /H₂ O (FIG. 6). Theacetal (-)-15 largely remained intact while the debenzylated alcohol(-)-25 was formed in 83% yield.

As shown in FIG. 7, we again utilized the TBS ether (+)-17 for thepreparation of C from common precursor (+)-5. Oxidative cleavage of thePMB group (DDQ, CH₂ Cl₂, H₂ O) provided alcohol 26 in variable (60-86%)yields, accompanied by the corresponding lactone. Debenzylation withPearlman's catalyst afforded (+)-26 in 92% yield. Exposure of thealcohol to SO₃.pyr furnished aldehyde (+)-27 (98% yield), which in turnwas converted to dithiane (+)-28 (79%). In the latter step, ourmodification of the Evans protocol for dithiane generation (TMSSCH₂)₂CH₂, ZnCl₂, Et₂ O! minimized elimination of the TBS ether to form theα,β-unsaturated amide. Following reduction to aldehyde (+)-29 with DIBAL(91% yield), dimethyl acetal formation gave (+)-30 (99%). The couplingof dithiane 30 with R-(-)-glycidyl benzyl ether (-)-31! then affordedalcohol (-)-32 in 79% yield. Unmasking of the ketone moiety (CF₃ CO₂)₂IPh, 80%! and Evans stereocontrolled reduction (97%) provided the antidiol (-)-34, which embodied all of the stereocenters in fragment C.

Acid-catalyzed cyclization of (-)-34 (TsOH, room temperature) providedmethoxy pyran 35 in 87% yield as a 1:2 mixture of and β anomers (FIG.8). Debenzylation (H₂, Pd/C) of 36 afforded alcohol 37 quantitatively.Exposure to EtSH and MgBr₂ in Et₂ O then gave a separable 6:1 mixture ofβ ethyl hemithioacetal (+)-38 and its α anomer in 83% yield. Swernoxidation of (+)-38 furnished the final fragment (+)-C in 86% yield.

Synthesis of the desired B segment (-)-B preferably was achieved bydirect olefination of aldehyde (+)-18 (41%, 6:1 Z/E) (FIG. 9), followedby chromatographic removal of the undesired E cross coupling product.Reaction of (-)-B with the organozinc derivative of (-)-A (FIG. 10) wasachieved by premixing iodide A with dried solid ZnCl₂ (ether, -78° C.)before addition of t-BuLi. It is believed that three equivalents oft-BuLi are required for complete consumption of (-)-A, probably becausethe first equivalent reacts with ZnCl₂. This modification increased theyield to 66% after flash chromatography.

Conversion of the Z trisubstituted olefin (-)-39 to the phosphoniumiodide (-)-49 began with selective removal of the PMB group, as in ourmodel study (DDQ, CH₂ Cl₂, H₂ O), furnishing (-)-40 in 87% yield (FIG.11). As shown in FIG. 12, alcohol (-)-40 furnished the requisite iodide42 almost exclusively, as indicated by NMR examination of the crudematerial. The very sensitive iodide was used without purification.Thorough mixing of iodide 42 with i-Pr₂ NEt (3 equiv) followed byexposure to excess PPh₃ (15 equiv) without solvent at 80° C. generated(-)-49 in 37% yield for the two steps. The major by-product wascharacterized as (-)-50 (35% yield). The unsaturated model alcohol(+)-44 similarly afforded the Wittig salt (+)-46 in low yield (FIG. 13),whereas the saturated derivative (+)-51 gave phosphonium iodide (+)-53almost quantitatively.

As shown in FIG. 14, assembly of the discodermolide backbone entailedWittig coupling of aldehyde C with the ylide derived from AB phosphoniumsalt (-)-49 to install the C(8,9) Z alkene in (-)-54 (>49:1 Z/E, 76%yield). DIBAL reduction (88% yield) followed by oxidation of theresultant primary alcohol (-)-55 then produced aldehyde (-)-56 (96%).The terminal Z diene (-)-57 was elaborated via the Yamamoto protocol in70% yield with excellent selectivity (16:1 Z/E). After flashchromatography, hydrolysis of the hemithio acetal and mild DMSO/Ac₂ Ooxidation provided lactone (-)-58 in 82% yield for the two steps.Removal of the PMB group (DDQ, CH₂ Cl₂, H₂ O, 95% yield) and carbamateformation (Cl₃ CONCO, CH₂ Cl₂, neutral Al₂ O₃, 83%) afforded tris(TBSether) (-)-60. Final deprotection with 48% HF/CH₃ CN (1:9) furnished(-)-discodermolide, identical with an authentic sample (FIG. 15).

Preferred processes according to the invention involve contacting aphosphonium salt of formula I with base and an alkylthiol of formula II:##STR18## to form a diene of formula III: ##STR19## wherein: R₁, R₂, R₃,R₆, R₇, R₈, R₁₁, R₁₂, and R₁₃ are, independently, C₁ -C₁₀ alkyl;

X is a halogen;

Z, Z₁, and Z₂ are, independently, O, S or NR';

R₄, R₉, R₁₄, and R₁₅ are, independently, acid labile hydroxyl protectinggroups;

R₅ is C₆ -C₁₄ aryl;

Y is O, S or NR';

R' and R₁₆ are, independently, hydrogen or C₁ -C₆ alkyl; and

R₁₈ is C₆ -C₁₄ aryl.

Such procedures preferably are run in solvents such as tetrahydrofuranat -78° C.-0° C. Suitable bases for such procedures include sodiumhexamethyldisilazide, potassium hexamethyldisilazide, and n-butyllithiumwith hexamethylphosphoramide.

Alkyl groups according to the invention include but are not limited tostraight chain and branched chain hydrocarbons such as methyl, ethyl,propyl, pentyl, isopropyl, 2-butyl, isobutyl, 2-methylbutyl, andisopentyl moieties having 1 to about 10 carbon atoms, preferably 1 toabout 6 carbon atoms. Cycloalkyl groups are cyclic hydrocarbons having 3to about 10 carbon atoms such as cyclopentyl and cyclohexyl groups.Heterocycloalkyl groups are cycloalkyl groups which include at least oneheteroatom (i.e., an atom which is not carbon, such as O, S, or N) intheir cyclic backbone. Alkenyl groups according to the invention arestraight chain or branched chain hydrocarbons that include one or morecarbon--carbon double bonds. Preferred alkenyl groups are those having 2to about 10 carbon atoms. Alkyl, cycloalkyl, heterocycloalkyl, andalkenyl groups according to the invention optionally can be unsubtitutedor can bear one or more substituents such as, for example, halogenhydroxyl, amine, and epoxy groups.

Aryl groups according to the invention are aromatic and heteroaromaticgroups having 6 to about 14 carbon atoms, preferably from 6 to about 10carbon atoms, including, for example, naphthyl, phenyl, indolyl, andxylyl groups and substituted derivatives thereof, particularly thosesubstituted with amino, nitro, hydroxy, methyl, methoxy, thiomethyl,trifluoromethyl, mercaptyl, and carboxy groups. Alkaryl groups aregroups that contain alkyl and aryl portions and are covalently bound toother groups through the alkyl portion, as in a benzyl group.

Protecting groups are known per se as chemical functional groups thatcan be selectively appended to and removed from functionality, such ashydroxyl and amine groups, present in a chemical compound to render suchfunctionality inert to certain chemical reaction conditions to which thecompound is exposed. See, e.g., Greene and Wuts, Protective Groups inOrganic Synthesis, 2d edition, John Wiley & Sons, New York, 1991.Numerous hyroxyl protecting groups are known in the art, including theacid-labile t-butyldimethylsilyl, diethylisopropylsilyl, andtriethylsilyl groups and the acid-stable aralkyl (e.g., benzyl),triisopropylsilyl, and t-butyldiphenylsilyl groups. Useful amineprotecting groups include the allyloxycarbonyl (Alloc),benzyloxycarbonyl (CBz), chlorobenzyloxycarbonyl, t-butyloxycarbonyl(Boc), fluorenylmethoxycarbonyl (Fmoc), isonicotinyloxycarbonyl (i-Noc)groups.

The methods of the invention involve also are directed to the synthesisof alkenes of formula IV: ##STR20## by contacting organometallicreagents of formula Va: ##STR21## with vinyl halides of formula VIa:##STR22## wherein M is Li, Cu, Mg, or Zn, and R₁₀ is an acid stablehydroxyl protecting group. Alternatively, a vinyl halide of formula Vb:##STR23## is contacted with an organometallic compound of formula VIb:##STR24## VIb, which appears above. Such reactions preferably areperformed in the presence of a palladium-containing catalyst such asPd(PPh₃)₄, Pd(Cl₂) (PPh₃)₂, Pd(Cl₂) (dppf)₂.

In yet another aspect, the synthetic methods of the invention aredirected to the preparation of lactones having formula VII: ##STR25## bycontacting a diene of formula VIIIa: ##STR26## with an organometalliccompound having formula Va wherein R₂₄ is hydrogen and R₂₅ is hydrogenor an acid stable hydroxyl protecting group. Alternatively, anorganometallic compound having formula VIIIb is contacted with a vinylhalide having formula Vb. ##STR27## The reaction of compounds havingformulas V and VIII preferably is performed in ether in the presence ofa palladium- or nickel-containing catalyst.

The methods of the invention also involve producing dienes havingformula VIIIa by contacting phosphonium salts having formula IX:##STR28## with a base such as sodium hexamethyl disilazide and analkylthiol compound having formula II. Such procedures preferably arerun in solvents such as tetrahydrofuran at -78° C.-0° C. Suitable basesfor such procedures include sodium hexamethyldisilazide, potassiumhexamethyldisilazide, and n-butyllithium with hexamethylphosphoramide.

Although preferred synthetic methods are those directed to(+)-discodermolide and compounds having like stereochemistry, thoseskilled in the art will recognize that the methods disclosed herein canbe readily adapted to the synthesis of antipodal compounds such as, forexample, (-)-discodermolide, and vice versa. All such synthetic methodsare within the scope of the present invention.

The present invention provides compounds which mimic the chemical and/orbiological activity of the discodermolides. In preferred embodiments,such compounds have formula XI: ##STR29## where R₃₀ is substituted orunsubstituted C₁ -C₁₀ alkyl or a moiety formula XII or XIII: ##STR30##where A is C₁ -C₂₀ alkyl, --CH₂ NH(T) or a moiety of formula XIV:##STR31## wherein T is peptide having 1 to about 10 amino acids;

R₃₂, R₄₀, R₄₂, R₄₃, R₄₆, R₄₇, and R₄₈ are, independently, hydrogen or C₁-C₆ alkyl;

R₄₁ is a side chain of an amino acid;

W₁ and W₂ are, independently, --OR₄₉ or --NHP₁ ;

P₁ is hydrogen or an amine protecting group;

R₃₃ and R₃₆ are, independently, hydrogen, C₁ -C₁₀ alkyl, --OR₅₀, ═O ortogether form --CH₂ --CH₂ --;

R₃₄ and R₃₅ are, independently, hydrogen or together form--C(H)═C(H)--C(H)═C(H)--;

R₃₉ is --OR₅₁ or --CH₂ --R₅₁ ;

R₃₁ and R₄₄ are, independently, C₁ -C₁₀ alkyl;

Q₁ and Q₂ are, independently, hydrogen, --OR_(Q), --NHR₅₂, --OC(═O)NH₂or together form --O--C(O)--NH--;

R_(Q) is hydrogen or a hydroxyl protecting group;

R₅₁ is substituted or unsubstituted C₁ -C₁₄ aryl, tetrahydropyranyl,furanosyl, pyranosyl, C₃ -C₁₀ lactonyl or 2-pyranonyl;

R₄₅ is C₁ -C₆ alkenyl, C₁ -C₆ alkyl, C₆ -C₁₄ aryl, C₂ -C₁₀heterocycloalkyl, C₃ -C₁₀ cycloalkyl, or C₇ -C₁₅ aralkyl; and

R₄₉, R₅₀, and R₅₂ are, independently, hydrogen or C₁ -C₆ alkyl.

Some preferred compounds having formula XI are shown in FIGS. 33-36.

The term amino acid as used herein is intended to include allnaturally-occurring and synthetic amino acids known in the art. Ingeneral, amino acids have structure H₂ N--CH(R_(c))--C(O)OH where R_(c)is the amino acid side chain. Representative, naturally-occurring sidechains are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________    CH.sub.3           CH.sub.3 CH.sub.2 SCH.sub.2 CH.sub.2                       HOCH.sub.2         HOCH.sub.2 CH.sub.2                                        C.sub.6 H.sub.5 CH.sub.2                                                                         CH.sub.3 CH.sub.2 (OH)                                     HOC.sub.6 H.sub.5 CH.sub.2                                                                       HO.sub.2 CCH.sub.2 NH.sub.2 C(O)CH.sub.2                    ##STR32##                                                                                        ##STR33##                                                  ##STR34##         HCO.sub.2 CH.sub.2 CH.sub.2  NH.sub.2 C(O)CH.sub.2                            CH.sub.2  (CH.sub.3).sub.2 CH (CH.sub.3).sub.2                                CHCH.sub.2  CH.sub.3 CH.sub.2 CH.sub.2                      ##STR35##         H.sub.2 NCH.sub.2 CH.sub.2 CH.sub.2  H.sub.2 NC(NH)NHCH                       .sub.2 CH.sub.2 CH.sub.2  H.sub.2 NC(O)NHCH.sub.2                             CH.sub.2 CH.sub.2  CH.sub.3 CH.sub.2 CH(CH.sub.3)          HSCH.sub.2         CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                        HO.sub.2 CCH(NH.sub.2)CH.sub.2 SSCH.sub.2                                                        H.sub.2 NCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2               CH.sub.3 CH.sub.2                                                             CH.sub.3 SCH.sub.2 CH.sub.2                                                   __________________________________________________________________________

Hydrophobic amino acid side chains are preferred, including the CH₃ --,C₆ H₅ --CH₂ --, CH₃ --CH₂ --, CH₃ --S--CH₂ --CH₂ --, (CH₃)₂ --CH--,(CH₃)₂ --CH--CH₂ --, CH₃ --CH₂ --CH(CHH₃)--, and CH₃ --CH₂ --CH₂ --CH₂-- side chains. Peptides according to the invention are linear,branched, or cyclic chemical structures containing at least 2 covalentlybound amino acids.

Certain compounds of the invention contain amino groups and, therefore,are capable of forming salts with various inorganic and organic acids.Such salts are also within the scope of this invention. Representativesalts include acetate, adipate, benzoate, benzenesulfonate, bisulfate,butyrate, citrate, camphorate, camphorsulfonate, ethanesulfonate,fumarate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, methanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nitrate, oxalate, pamoate,persulfate, picrate, pivalate, propionate, succinate, sulfate, tartrate,tosylate, and undecanoate. The salts can be formed by conventionalmeans, such as by reacting the free base form of the product with one ormore equivalents of the appropriate acid in a solvent or medium in whichthe salt is insoluble, or in a solvent such as water which is laterremoved in vacuo or by freeze drying. The salts also can be formed byexchanging the anions of an existing salt for another anion on asuitable ion exchange resin.

The compounds of the invention can be admixed with carriers, excipients,and/or diluents to form novel compositions. Such compositions can beused in prophylactic, diagnostic, and/or therapeutic techniques. Byadministering an effective amount of such a composition, prophylactic ortherapeutic responses can be produced in a human or some other typemammal. It will be appreciated that the production of prophylactic ortherapeutic responses includes the initiation or enhancement ofdesirable responses, as well as the mitigation, cessation, orsuppression of undesirable responses. The compositions of the inventionare expected to find use, for example, in the inhibition of undesiredcell proliferation (e.g., cancer) and in the inhibition of rejection inorgan transplantation procedures. (See, e.g., Longley, et al.,Transplantation 1991, 52, 650 and 656).

Compositions of the invention can be prepared by any of the methods wellknown in the pharmaceutical art, for example, as described inRemington's Pharmaceutical Sciences (Mack Pub. Co., Easton, Pa., 1980).The compositions can include a compound of the invention as an activeingredient in admixture with an organic or inorganic carrier orexcipient suitable, for example, for oral administration. Other suitablemodes of administration will be apparent to those skilled in the art.The compound of the invention can be compounded, for example, with theusual non-toxic, pharmaceutically acceptable carriers for tablets,pellets, capsules, solutions, suppositories, suspensions, and any otherform suitable for use. The carriers which can be used are water,glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea and other carriers suitable for use in manufacturingpreparations, in solid, semisolid, or liquid form, and in additionauxiliary, stabilizing, thickening and coloring agents and perfumes maybe used. The compound of the invention is included in the pharmaceuticalcomposition in an amount sufficient to produce the desired effect uponthe process or condition of diseases.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch and preferably corn, potato or tapioca starch, alginicacid and certain complex silicates, together with granulation binderslike polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tableting purposes. Solid compositions ofa similar type may also be employed as fillers in appropriately soluble(e.g. gelatin) capsules; preferred materials in this connection alsoinclude lactose or milk sugar as well as high molecular weightpolyethylene glycols.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient may be combined with varioussweetening or flavoring agents, coloring matter or dyes, and, if sodesired, emulsifying and/or suspending agents as well, together withsuch diluents as water, ethanol, glycerin and various like combinationsthereof.

For parenteral administration, suspensions containing a compound of theinvention in, for example, aqueous propylene glycol can be employed. Thesuspensions should be suitably buffered (preferably pH>8) if necessaryand the liquid diluent first rendered isotonic. The aqueous suspensionsare suitable for intravenous injection purposes. The preparation of suchsuspensions under sterile conditions is readily accomplished by standardpharmaceutical techniques well-known to those skilled in the art.Additionally, it is possible to administer the compounds of theinvention topically and this may preferably be done by way of creams,jellies, gels, pastes, ointments and the like, in accordance withstandard pharmaceutical practice.

The compounds of the invention can be employed as the sole active agentin a pharmaceutical composition or can be used in combination with otheractive ingredients, e.g., other agents useful in diseases or disorders.

The amount of active ingredient that is to be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. The specificdose level for any particular patient will depend on a variety offactors including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination, and theseverity of the particular disease undergoing therapy. In someinstances, dosage levels below the lower limit of the aforesaid rangemay be more than adequate, while in other cases still larger doses maybe employed without causing any harmful side effects provided that suchhigher dose levels are first divided into several small doses foradministration throughout the day. The concentrations of the activeingredient in therapeutic compositions will vary depending upon a numberof factors, including the dosage of the drug to be administered, thechemical characteristics (e.g., hydrophobicity) of the activeingredient, and the route of administration. Typical dose ranges arefrom about 285 μg/kg of body weight per day in three divided doses; apreferred dose range is from about 42 μg/kg to about 171 μg/kg of bodyweight per day. The preferred dosage to be administered is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected, andformulation of the compound excipient, and its route of administration,as well as other factors, including bioavailability, which is in turninfluenced by several factors well known to those skilled in the art.

Additional objects, advantages, and novel features of this inventionwill become apparent to those skilled in the art upon examination of thefollowing examples thereof, which are not intended to be limiting.

All reactions were carried out in oven-dried or flame-dried glasswareunder an argon atmosphere, unless otherwise noted. All solvents werereagent grade. Diethyl ether and tetrahydrofuran (THF) were freshlydistilled from sodium/benzophenone under argon before use.Dichloromethane, benzene and diisopropyl amine were freshly distilledfrom calcium hydride before use. Triethylamine and diisopropylethylaminewere distilled from calcium hydride and stored over potassium hydroxide.Hexamethylphosphoramide was freshly distilled from calcium hydride.Anhydrous pyridine, dimethylformamide and dimethyl sulfoxide werepurchased from Aldrich and used without purification. n-Butyllithium andt-butyllithium were purchased from Aldrich and standardized by titrationwith diphenylacetic acid.

Unless stated otherwise all reactions were magnetically stirred andmonitored by thin layer chromatography using 0.25 mm E. Merck pre-coatedsilica gel plates. Flash column chromatography was performed with theindicated solvents using silica gel-60 (particle size 0.040-0.062 mm)supplied by E. Merck. Yields refer to chromatographically andspectroscopically pure compounds, unless otherwise stated.

All melting points were determined on a Bristoline heated-stagemicroscope or a Thomas-Hoover apparatus and are corrected. The IR andNMR were obtained for CHCl₃ and CDCl₃ solutions respectively unlessotherwise noted. Infrared spectra were recorded with a Perkin-ElmerModel 283B spectrometer using polystyrene as an external standard.Proton NMR spectra were recorded on a Bruker AM-500 spectrometer.Carbon-13 NMR spectra were recorded on a Bruker AM-500 or AM-250spectrometer. Chemical shifts are reported relative to internaltetramethylsilane (d 0.00) for proton and chloroform δ77.0) or benzene(δ128.0) for carbon-13. Optical rotations were obtained with aPerkin-Elmer model 241 polarimeter in the solvent indicated.High-resolution mass spectra were obtained at the University ofPennsylvania Mass Spectrometry Service Center on either a VG micromass70/70H high resolution double-focusing electron impact/chemicalionization spectrometer or a VG ZAB-E spectrometer. Microanalyses wereperformed by Robertson Laboratories, Madison, N.J. Single-crystal X-raydiffraction structure determination were performed at the University ofPennsylvania using an Enraf Nonius CAD-4 automated diffractometer. Highperformance liquid chromatography (HPLC) was performed using a Ranincomponent analytical/semi-prep system.

EXAMPLE 1 Alcohol (-)-8

p-Methoxybenzyl alcohol (200 g, 1.45 mol) was added to a suspension ofNaH (60% in mineral oil; 5.82 g, 0.146 mol) in anhydrous ether (450 mL)over 1 h at room temperature. The mixture was stirred for 1 h and cooledto 0° C. Trichloroacetonitrile (158 mL, 1.58 mol) was then introducedover 80 min. After 1.5 h the solution was concentrated with the waterbath temperature maintained below 40° C. The residue was treated with amixture of pentane (1.5 L) and MeOH (5.6 mL), stirred at roomtemperature for 30 min, and filtered through a short Celite column.Concentration gave the trichloroimidate (394.3 g) as a red oil which wasused without further purification.

A solution of (R)-(-)-Roche ester (124.7 g, 1.06 mol) in CH₂ Cl₂/cyclohexane (1:2, 1.5 L) was cooled to 0° C. and treated withtrichloroimidate (364.3 g) and PPTS (13.3 g, 52.9 mmol). After 3 h, themixture was warmed to room temperature, stirred for 40 h, andconcentrated. Filtration through a short silica column (20% ethylacetate/hexane) afforded the ester (303.5 g) as a slight yellow oil.

The ester (303.5 g) was divided into three portions for the nextreaction. In each preparation, solution of crude ester (112.8 g) inanhydrous THF (1.0 L) was cooled to 0° C. and LiAlH₄ (1.0M in THF, 560mL, 0.560 mol) was added over 1 h.

The mixture was warmed gradually to room temperature and stirred for 24h. After dilution with ether (1.0 L) the mixture was cooled to 0° C. andquenched carefully with saturated aqueous Rochelle's salt (20 mL). Theresultant mixture was then transferred to a 4-L flask, diluted withether (1.0 L), and treated with additional Rochelle's solution (ca. 300mL) with shaking untill a solid precipitated. The solution was filtered,concentrated, and the residue (including the aqueous layer) was dilutedwith ether (700 mL), dried over Na₂ SO₄, filtered and concentrated. Thecrude products of the three reactions were combined and distilled undervacuum, furnishing (-)-8 (142.7 g, 74% yield for two steps) as acolorless oil: α!²³ _(D) -16.9° (c 1.28, CHCl₃); IR (CHCl₃) 3510 (m),3015 (s), 2965 (s), 2940 (s), 2920 (s), 2870 (s), 2840 (m), 1618 (s),1590 (m), 1517 (s), 1470 (s), 1445 (m), 1423 (m), 1365 (m), 1305 (s),1250 (s), 1178 (s), 1092 (s), 1037 (s), 826 (m), 814 (m), 718 (w), 710(w) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.23 (d, J=8.6 Hz, 2 H), 6.86 (d,J=8.6 Hz, 2 H), 4.43 (ABq, J_(AB) =11.7 Hz, Δδ_(AB) =13.2 Hz, 2 H), 3.78(s, 3 H), 3.61-3.54 (m, 2 H), 3.53 (ddd, J=9.1, 4.7, 0.8 Hz, 1 H), 3.38(dd, J=9.1, 7.9 Hz, 1 H), 2.60 (br s, 1 H), 2.08-1.98 (m, 1 H), 0.90 (d,J=7.0 Hz, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 159.2, 130.2, 129.2, 113.8,75.0, 73.0, 67.7, 55.2, 35.6, 13.4; high resolution mass spectrum (CI,NH₃) m/z 210.1252 M⁺ ; calcd for C₁₂ H₁₈ O₃ : 210.1256!.

Anal. Calcd for C₁₂ H₁₈ O₃ : C, 68.54; H. 8.63. Found: 5 C, 68.41; H,8.60.

EXAMPLE 2 Aldol (+)-10

A solution of DMSO (40.0 mL, 564 mmol) in CH₂ Cl₂ (1.0 L) was cooled to-78° C. and oxalyl chloride (23.0 mL, 263 mmol) was added over 1 h.After an additional 15 min, a cooled (-78° C.) solution of alcohol (-)-8(38.0 g, 181 mmol) in CH₂ Cl₂ (50 mL) was introduced via a cannula over15 min (20 mL rinse) and the resultant milky mixture was stirred 0.5 hfurther at -78° C. i-Pr₂ NEt (150 mL, 861 mmol) was then added over 15min. The mixture was stirred for 30 min, slowly warmed to roomtemperature (70 min), and quenched with aqueous NaHSO₄ (1.0M, 1.0 L).The organic phase was concentrated, diluted with ether (500 mL), washedwith water (6×500 mL), dried over MgSO₄, filtered and concentrated togive the corresponding aldehyde (38.0 g) as a colorless oil.

A solution of oxazolidinone (+)-9 (44.3 g, 190 mmol) in CH₂ Cl₂ (500 mL)was cooled to 0° C. n-Bu₂ BOTf (1.0M in CH₂ Cl₂, 199.0 mL, 199 mmol) wasintroduced over 0.5 h, followed by addition of NEt₃ (30.2 mL, 217 mmol)over 10 min. The mixture was stirred at 0° C. for 0.5 h and cooled to-78 C. A precooled (-78° C.) solution of the above aldehyde in CH₂ Cl₂(100 mL) was then added via a cannula over 30 min (2×20 mL rinse). After2 h at -78° C. and 2 h at 0° C., the reaction was quenched with pH 7phosphate buffer (200 mL). The mixture was slowly treated with asolution of 30% H₂ O₂ in MeOH (1:2, 600 mL) at 0° C., stirred overnightat room temperature, and concentrated. The residue was extracted withethyl acetate (3×250 mL) and the combined extracts were washed withsaturated aqueous NaHCO₃ and water (500 mL each), dried over MgSO₄,filtered and concentrated. Flash chromatography (30% ethylacetate/hexane) provided (+)-10 (70.9 g, 89% yield from 8) as acolorless oil: α!²³ _(D) +278° (c 0.49, CHCl₃); IR (CHCl₃) 3470 (w, br),3020 (m), 2980 (m), 2940 (m), 2920 (m), 2880 (m), 1790 (s), 1705 (m),1620 (m), 1590 (w), 1520 (m), 1485 (w), 1460 (m), 1390 (m), 1360 (m),1305 (w), 1230 (br, s), 1110 (m), 1080 (m), 1035 (m), 985 (m), 970 (m),820 (w), 695 (w) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.33-7.30 (m, 2 H),7.27-7.19 (m, 5 H), 6.85 (d, J=8.7 Hz, 2 H), 4.67-4.63 (m, 1 H), 4.42(apparent s, 2 H), 4.14 (apparent d, J=5.0 Hz, 2 H), 3.93 (qd, J=6.9,3.4 Hz, 1 H), 3.85 (ddd, J=8.2, 3.1, 3.1 Hz, 1 H), 3.78 (s, 3 H), 3.69(d, J=2.8 Hz, 1 H), 3.54 (apparent t, J=9.3 Hz, 1 H), 3.54 (dd, J=21.1,9.2 Hz, 1 H), 3.28 (dd, J=13.4, 3.2 Hz, 1 H), 2.76 (dd, J=13.4, 9.6 Hz,1 H), 1.98-1.93 (m, 1 H), 1.25 (d, J=6.9 Hz, 3 H), 0.94 (d, J=7.0 Hz, 3H); ¹³ C NMR (125 MHZ, CDCl₃) d 176.1, 159.2, 153.0, 135.3, 129.9,129.3, 129.2, 128.8, 127.2, 113.7, 75.3, 74.5, 73.1, 66.0, 55.5, 55.2,40.6, 37.7, 35.9, 13.5, 9.7; high resolution mass spectrum (CI, NH₃) m/z442.2243 (M+H)⁺ ; calcd for C₂₅ H₃₂ NO₆ : 442.2229!.

Anal. Calcd for C₂₅ H₃₁ NO₆ : C, 68.01; H, 7.08. Found: C, 67.81; H,7.26.

EXAMPLE 3 Common Precursor (+)-5

A suspension of N,O-Dimethylhydroxylamine hydrochloride (46.9 g, 481mmol) in THF (250 mL) was cooled to 0° C. and AlMe₃ (2.0M in hexane, 240mL, 480 mmol) was added over 30 min. The resultant solution was warmedto room temperature, stirred for 0.5 h and then cooled to -30° C. Asolution of oxazolidinone (+)-10 (70.9 g, 161 mmol) in THF (150 mL) wasintroduced over 20 min via cannula (20 mL rinse). After 3 h, thesolution was poured slowly into a mixture of aqueous HCl (1.0N, 1.2 L)and CH₂ Cl₂ (1.0 L) at 0° C. and the mixture was shaken vigorously for 1h. The aqueous phase was extracted with CH₂ Cl₂ (2×500 mL) and thecombined organic extracts were washed with water (3×1.0 L), dried overMgSO₄, filtered and concentrated. The crude material was taken up inethyl acetate/hexane (1:3, 150 mL) with vigorous stirring to precipitatemost of the chiral auxiliary. Filtration, concentration and flashchromatography (20% acetone/hexane) afforded (+)-5 (46.2 g, 88% yield)as a colorless oil: α!²³ _(D) +144° (c 0.41, CHCl₃); IR (CHCl₃) 3470 (m,br), 3010 (s), 2975 (s), 2945 (s), 2915 (s), 2870 (s), 2845 (m), 1680(s), 1590 (w), 1515 (s), 1465 (s), 1425 (m), 1390 (m), 1365 (m), 1310(m), 1250 (s), 1180 (s), 1150 (m), 1090 (s), 1040 (s), 1000 (s), 825 (m)cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.25 (d, J=8.6 Hz, 2 H), 6.86 (d,J=8.7 Hz, 2 H), 4.44 (ABq, J_(AB) =11.6 Hz, Δδ_(AB) =17.1 Hz, 2 H), 3.95(d, J=2.8 Hz, 1 H), 3.79 (s, 3 H), 3.70 (ddd, J=8.2, 3.2, 3.2 Hz, 1 H),3.66 (s, 3 H), 3.62 (dd, J=9.0, 4.0 Hz, 1 H), 3.53 (dd, J=9.1, 5.9 Hz, 1H), 3.17 (s, 3 H), 3.04 (m, 1 H), 1.91-1.84 (m, 1 H), 1.17 (d, J=7.0 Hz,3 H), 0.98 (d, J=6.9 Hz, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 178.0, 159.0,130.6, 129.1, 113.7, 113.6, 73.8, 72.8, 72.6, 61.3, 55.1, 36.5, 36.0,14.2, 10.4; high resolution mass spectrum (CI, NH₃) m/z 326.1962 (M+H)⁺; calcd for C₁₇ H₂₈ NO₅ : 326.1967!.

Anal. Calcd for C₁₇ H₂₇ NO₅ : C, 62.74; H, 8.36. Found: C, 62.74; H,8.24.

EXAMPLE 4 Weinreb Amide (-)-11

A mixture of common precursor (+)-5 (337.3 mg, 1.04 mmol), 4 Å molecularsieves (344 mg), and CH₂ Cl₂ (10 mL) was cooled to 0° C. and treatedwith DDQ (310.3 mg, 1.37 mmol). After 1.5 h, the mixture was filteredthrough a short Celite column (50% ethyl acetate/hexane). The filtratewas washed with saturated aqueous NaHCO₃ and water (100 mL each), driedover MgSO₄, filtered and concentrated. Flash chromatography (30% ethylacetate/hexane) provided (-)-11 (255.6 mg, 76% yield) as a colorlessoil: α!²³ _(D) -339° (c 0.520, CHCl₃); IR (CHCl₃) 3010 (s), 2970 (s),2940 (m), 2880 (m), 2840 (m), 1663 (s), 1620 (s), 1592 (w), 1520 (s),1466 (s), 1447 (m), 1425 (m), 1393 (s), 1375 (s), 1307 (m), 1253 (s),1178 (s), 1120 (s), 1083 (s), 1035 (s), 1015 (m), 1000 (s), 930 (w), 830(m), 700 (w), 660 (w), 620 (w) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.41(d, J=8.8 Hz, 2 H), 6.87 (d, J=8.8 Hz, 2 H), 5.46 (s, 1 H) 4.04 (dd,J=11.3, 4.7 Hz, 1 H), 3.82 (dd, J=9.8, 6.5 Hz, 1 H), 3.79 (s, 3 H), 3.71(s, 3 H), 3.51 (apparent t, J=11.2 Hz, 1 H), 3.19 (s, 3 H), 3.21-3.14(m, 1 H), 1.98-1.92 (m, 1 H), 1.27 (d, J=7.0 Hz, 3 H), 0.75 (d, J=6.8Hz, 3 H); i3C NMR (125 MHZ, CDCl₃) d 175.8, 159.8, 131.2, 127.2, 113.5,100.7, 82.8, 72.8, 61.3, 55.3, 39.0, 33.8, 32.6, 13.1, 12.4; highresolution mass spectrum (CI, NH₃) m/z 323.1736 M⁺ ; calcd for C₁₇ H₂₅NO₅ : 323.1732!.

Anal. Calcd for C₁₇ H₂₅ NO₅ : C, 63.14; H, 7.79. Found: C, 63.18; H,7.74.

EXAMPLE 5 Aldehyde (-)-12

A solution of amide (-)-11 (2.07 g, 6.40 mmol) in THF (70 mL) was cooledto -78° C. and LiAlH₄ (1.0M in THF, 3.40 mL, 3.40 mmol) was added over15 min. After 10 min at -78° C. and 10 min at 0° C., the mixture wasquenched with MeOH (1.0 mL), and partitioned between ethyl acetate andsaturated aqueous Rochelle's salt (100 mL each). The organic phase waswashed with brine (100 mL), dried over MgSO₄, filtered and concentrated.Flash chromatography (15% ethyl acetate/hexane) gave (-)-12 (1.38 g, 80%yield) as a colorless oil: α!²³ _(D) -7.8° (c 0.46, CHCl₃); IR (CHCl₃)3015 (m), 2970 (m), 2940 (m), 2840 (m), 1735 (s), 1725 (s), 1615 (m),1590 (w), 1520 (s), 1460 (s), 1390 (m), 1370 (m), 1305 (m), 1250 (s),1170 (s), 1115 (s), 1085 (s), 1035 (s), 990 (m), 960 (m), 830 (m) cm⁻¹ ;¹ H NMR (500 MHZ, CDCl₃) d 9.74 (apparent s, 1 H), 7.32 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.7 Hz, 2 H), 5.46 (s, 1 H), 4.13 (dd, J=11.5, 4.8 Hz, 1H), 4.05 (dd, J=10.4, 2.6 Hz, 1 H), 3.77 (s, 3 H), 3.56 (apparent t,J=11.1 Hz, 1 H), 2.56 (qd, J=7.1, 2.6 Hz, 1 H), 2.15-2.03 (m, 1 H), 1.23(d, J=7.1 Hz, 3 H), 0.80 (d, J=6.7 Hz, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d204.0, 159.9, 130.7, 127.2, 113.5, 100.9, 81.6, 72.8, 55.2, 47.4, 30.3,11.9, 7.1; high resolution mass spectrum (CI, NH₃) m/z 265.1432 (M+H)⁺ ;calcd for C₁₅ H₂₁ O₄ : 265.1439!.

EXAMPLE 6 Aldol (+)-13

A solution of oxazolidinone (+)-9 (21.6 g, 92.7 mmol) in CH₂ Cl₂ (200mL) was cooled to 0° C. and n-Bu₂ BOTf (1.0M in CH₂ Cl₂, 86.1 mL, 86.1mmol) was added over 0.5 h, followed by addition of NEt₃ (15.7 mL, 112.5mmol) over 10 min. The mixture was stirred at 0° C. for 1 h and cooledto -78° C. A solution of aldehyde (-)-12 (17.5 g, 66.2 mmol) in CH₂ Cl₂(50 mL) was added over 10 min. After additional 20 min at -78° C. and 1h at 0° C., the reaction was quenched with pH 7 phosphate buffer (100mL) and MeOH (300 mL), then slowly treated with a solution of 30% H₂ O₂in MeOH (1:1, 100 mL) at 0° C. After 1 h, saturated aqueous Na₂ S₂ O₃(100 mL) was added. The mixture was concentrated and the residue wasextracted with ethyl acetate (3×250 mL). The combined extracts werewashed with saturated aqueous Na₂ S₂ O₃ aqueous NaHCO₃ (10w), brine (200mL each), dried over MgSO₄, filtered and concentrated. Flashchromatography (10% ethyl acetate/hexane) provided (+)-13 (26.3 g, 80%yield) as white crystals: mp 98°-100° C; α!²³ _(D) +13.5° (c 1.19,CHCl₃); IR (CHCl₃) 3690 (w), 3520 (w, br), 3020 (m), 2980 (m), 2940 (m),2880 (w), 2850 (m), 1790 (s), 1695 (m), 1620 (m), 1595 (w), 1525 (m),1505 (w), 1490 (w), 1465 (m), 1390 (s), 1365 (m), 1310 (m), 1260-1210(m, br), 1175 (m), 1120 (s), 1085 (m), 1040 (m), 1020 (m), 985 (m), 970(m), 930 (w), 830 (m), 700 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.35(d, J=8.7 Hz, 2 H), 7.31 (d, J=7.6 Hz, 2 H), 7.27 (d, J=7.2 Hz, 1 H),7.19 (d, J=7.7 Hz, 2 H), 6.84 (d, J=8.7 Hz, 2 H), 5.45 (s, 1 H),4.67-4.62 (m, 1 H), 4.14 (apparent d, J=5.3 Hz, 2 H), 4.08 (dd, J=11.4,4.8 Hz, 1 H), 4.07 (apparent t, J=4.1 Hz, 1 H), 4.04-3.99 (m, 1 H), 3.76(s, 3 H), 3.61 (dd, J=9.9, 2.2 Hz, 1 H), 3.51 (apparent t, J=11.1 Hz, 1H), 3.33 (d, J=1.3 Hz, 1 H), 3.21 (dd, J=13.4, 3.4 Hz, 1 H), 2.76 (dd,J=13.4, 9.4 Hz, 1 H), 2.12-2.06 (m, 1 H), 1.92-1.86 (m, 1 H), 1.31 (d,J=6.9 Hz, 3 H), 1.07 (d, J=7.0 Hz, 3 H), 0.74 (d, J=6.7 Hz, 3 H); ¹³ CNMR (125 MHZ, CDCl₃) d 177.1, 160.0, 152.7, 135.0, 131.0, 129.4, 128.9,127.40, 127.39, 113.6, 101.2, 85.8, 74.5, 73.0, 66.0, 55.2, 54.9, 39.8,37.7, 35.7, 30.4, 12.8, 11.7, 7.8; high resolution mass spectrum (CI,NH.) m/z 497.2410 M⁺ ; calcd for C₂₈ H₃₅ NO₇ : 497.2413!.

Anal. Calcd for C₂₈ H₃₅ NO₇ : C, 67.58; H, 7.09. Found: C, 67.42; H,7.02.

EXAMPLE 7 Acetal (+)-14

A solution of alcohol (+)-13 (26.3 g, 52.9 mmol) and 2,6-lutidine (11.1mL, 95.3 mmol) in CH₂ Cl₂ (150 mL) was cooled to -20° C. and TBSOTf(20.5 mL, 79.3 mmol) was added over 30 min. After additional 2 h at 0°C., the mixture was diluted with ether (300 mL), washed with aqueousNaHSO₄ (1.0M, 200 mL), brine (200 mL), dried over MgSO₄, filtered andconcentrated. Flash chromatography (gradient elution, 5%→10% ethylacetate/hexane) afforded (+)-14 (32.4 g, 100% yield) as a colorless oil:α!²³ _(D) +20.3° (c 1.32, CHCl₃); IR (CHCl₃) 3025 (m), 2970 (m), 2940(m), 2864 (m), 1788 (s), 1705 (m), 1620 (m), 1597 (w), 1524 (m), 1503(w), 1470 (m), 1447 (w), 1430 (w), 1395 (s), 1358 (m), 1307 (m), 1255(s), 1135 (m), 1120 (s), 1075 (m), 1030 (m), 985 (m), 976 (m), 930 (m),865 (m), 838 (s), 813 (m), 790 (m), 700 (m) cm⁻¹ ; ¹ H NMR (500 MHZ,CDCl₃) d 7.38 (d, J=8.7 Hz, 2 H), 7.30-7.12 (m, 5 H), 6.82 (d, J=8.7 Hz,2 H), 5.44 (s, 1 H), 4.30 (dddd, J=13.4, 7.3, 5.1, 5.1 Hz, 1 H), 4.11(dd, J=7.1, 4.0 Hz, 1 H), 4.02 (dd, J=11.2, 4.7 Hz, 1 H), 3.97 (dq,J=7.0, 7.0 Hz, 1 H), 3.80 (dd, J=8.9, 2.3 Hz, 1 H), 3.740 (apparent t,J=4.9 Hz, 1 H), 3.738 (s, 3 H), 3.48 (apparent t, J=11.1 Hz, 1 H), 3.27(apparent t, J=8.2 Hz, 1 H), 3.15 (dd, J=13.4, 3.2 Hz, 1 H), 2.59 (dd,J=13.4, 9.8 Hz, 1 H), 2.05 (apparent qd, J=7.4, 4.2 Hz, 1 H), 2.02-1.94(m, 1 H), 1.19 (d, J=6.9 Hz, 1 H), 1.04 (d, J=7.5 Hz, 3 H), 0.92 (s, 9H), 0.73 (d, J=6.7 Hz, 3 H), 0.05 (s, 3 H), 0.04 (s, 3 H); ¹³ C NMR (125MHZ, CDCl₃) d 175.6, 159.9, 152.4, 135.5, 132.0, 129.4, 128.8, 127.8,127.2, 113.4, 100.7, 80.7, 74.6, 73.1, 65.3, 55.3, 55.2, 41.4, 40.9,37.4, 30.6, 26.0, 18.1, 15.0, 12.7, 11.5, -4.0, -4.6; high resolutionmass spectrum (CI, NH,) m/z 612.3340 (M+H)⁺ ; calcd for C₃₄ H₅₀ NO₇ Si:612.3356!.

Anal. Calcd for C₃₄ H₄₉ NO7Si: C, 66.74; H. 8.07. Found: C, 66.69; H,7.98.

EXAMPLE 8 Alcohol (-)-15

A solution of acetal (+)-14 (32.0 g, 52.3 mmol) in THF (600 mL) wascooled to -30° C. and EtOH (6.14 mL, 105 mmol) was added, followed byaddition of LiBH₄ (2.0M in THF, 52.3 mL, 105 mmol) over 15 min. Afteradditional 1 h at 0° C. and 12 h at room temperature, the mixture wasdiluted with ether (1.0 L), quenched carefully with aqueous NaOH (1.0N,200 mL) and stirred for 2 h at room temperature. The layers wereseparated and the organic phase was washed with brine (500 mL), driedover Na₂ SO₄. filtered and concentrated. Flash chromatography (20% ethylacetate/hexane) provided (-)-15 (18.7 g, 81% yield) as a colorless oil:α!²³ _(D) -36.1° (c 1.15, CHCl₃); IR (CHCl₃) 3630 (w), 3480 (w, br),3010 (m), 2960 (s), 2940 (s), 2885 (m), 2860 (s), 1620 (m), 1594 (w),1523 (s), 1468 (s), 1445 (w), 1430 (w), 1395 (m), 1365 (m), 1307 (m),1255 (s), 1175 (m)), 1165 (m), 1150 (m), 1120 (s), 1080 (s), 1030 (s),990 (m), 968 (m), 910 (s), 860 (m), 833 (s), 700 (m), 645 (m) cm⁻¹ ; ¹ HNMR (500 MHZ, CDCl₃) d 7.36 (d, J=8.7 Hz, 2 H), 6.85 (d, J=8.8 Hz, 2 H),5.38 (s, 1 H), 4.08 (dd, J=11.2, 4.7 Hz, 1 H), 3.84 (dd, J=6.7, 1.9 Hz,1 H), 3.77 (s, 3 H), 3.53 (dd, J=9.9, 1.8 Hz, 1 H), 3.55-3.52 (m, 1 H),3.47 (apparent t, J=11.1 Hz, 1 H), 3.44 (dd, J=10.3, 6.2 Hz, 1 H),2.08-1.97 (m, 2 H), 1.94 (dqd, J=7.1, 7.1, 1.7 Hz, 1 H), 1.76 (br s, 1H), 1.02 (d, J=7.1, 3 H), 0.88 (s, 9 H), 0.84 (d, J=6.9 Hz, 3 H), 0.73(d, J=6.7 Hz, 3 H), 0.03 (s, 3 H), 0.00 (s, 3 H); ¹³ C NMR (125 MHZ,CDCl₃) d 159.8, 131.4, 127.3, 113.5, 101.0, 82.9, 74.3, 73.3, 66.3,55.2, 38.7, 37.8, 30.7, 26.1, 18.3, 12.2, 11.1, 10.7, -4.0, -4.2; highresolution mass spectrum (CI, NH,) m/z 439.2889 (M+H)⁺ ; calcd for C₂₄H₄₃ O₅ Si: 439.2879!.

Anal. Calcd for C₂₄ H₄₂ O₅ Si: C, 65.71; H, 9.65. Found: C, 65.51; H9.54.

EXAMPLE 9 Tosylate (-)-16

A solution of alcohol (-)-15 (5.00 g, 11.4 mmol) in anhydrous pyridine(30 mL) was cooled to 0° C. and treated with TsCl (3.91 g, 20.5 mmol).After 30 min at 0° C. and 5 h at room temperature, the reaction wasquenched with saturated aqueous NaHCO₃ (20 mL). The mixture was dilutedwith ether (200 mL), washed with aqueous NaHSO₄ (1.0M), aqueous NaHCO₃(10%), brine (200 mL each), dried over MgSO₄, filtered and concentrated.Flash chromatography (100 ethyl acetate/hexane) provided (-)-15 (6.76 g,100% yield) as white solid: mp 71°-72° C.; α!²³ _(D) -23.2° (c 1.42,CHCl₃); IR (CHCl₃) 3020 (m), 3000 (m), 2960 (s), 2935 (s), 2880 (m),2855 (s), 1617 (m), 1600 (m), 1590 (m), 1518 (m), 1495 (w), 1462 (s),1390 (m), 1360 (s), 1302 (m), 1250 (s), 1190 (s), 1178 (s), 1120 (s),1098 (s), 1085 (s), 1070 (s, 1032 (s), 963 (s), 900 (m), 830 (s), 810(s), 653 (m); ¹ H NMR (500 MHZ, CDCl₃) d 7.70 (d, J=8.3 Hz, 2 H), 7.34(d, J=8.7 Hz, 2 H), 7.25 (d, J=8.8 Hz, 2 H), 6.86 (d, J=8.7 Hz, 2 H),5.36 (s, 3 H), 4.07 (dd, J=11.2, 4.7 Hz, 1 H), 3.85 (dd, J=7.3, 2.7 Hz,1 H), 3.79 (s, 3 H), 3.71 (dd, J=7.1, 1.7 Hz, 1 H), 3.48 (dd, J=9.9, 1.4Hz, 1 H), 3.45 (apparent t, J=11.1 Hz, 1 H), 2.40 (s, 3 H), 2.15 (dqd,J=13.9, 7.0, 1.7 Hz, 1 H), 2.05-1.96 (m, 1 H), 1.83 (dqd, J=7.1, 7.1,1.6 Hz, 1 H), 0.94 (d, J=7.1 Hz, 3 H), 0.82 (s, 9 H), 0.81 (d, J=7.7 Hz,3 H), 0.69 (d, J=6.7 Hz, 3 H), -0.04 (s, 3 H), -0.11 (s, 3 H); ¹³ C NMR(125 MHZ, CDCl₃) d 159.8, 144.6, 133.2, 131.3, 129.7, 127.9, 127.3,113.5, 100.9, 82.0, 73.7, 73.2, 73.0, 55.2, 38.4, 35.5, 30.6, 26.0,21.6, 18.3, 12.2, 10.6, 10.3, -3.9, -4.3; high resolution mass spectrum(FAD, NBA) m/z 593.2955 (M+H)⁺ ; calcd for C₃₁ H₄₉ O₇ SSi: 593.2968!.

EXAMPLE 10 Fragment (-)-A

From Tosylate (-)-16: A solution of Tosylate (-)-16 (6.76 g, 11.4 mmol)in anhydrous DMF (50 mL) was treated with NaI (17.1 g, 114.0 mmol),heated at 60° C. for 1.5 h, and cooled to room temperature. The mixturewas diluted with ether (200 mL), washed with water (200 mL), saturatedaqueous Na₂ S₂ O₃ (100 mL), brine (200 mL), dried over MgSO₄, filteredand concentrated. Flash chromatography (3% ethyl acetate/hexane)provided (-)-A (5.87 g, 94% yield) as a colorless oil.

From Alcohol (-)-15: A solution of alcohol (-)-15 (4.70 g, 10.7 mmol),PPh₃ (4.21 g, 16.1 mmol) and imidazole (1.09 g, 16.1 mmol) inbenzene/ether (1:2, 75 mL) was treated with 12 (4.08 g, 16.1 mmol) undervigorous stirring. The mixture was stirred 1 h then diluted with ether(200 mL), washed with saturated Na₂ S₂ O₃, brine (100 mL each), driedover MgSO₄, filtered and concentrated. Flash chromatography (2% ethylacetate/hexane) furnished (-)-A (5.56 g, 95% yield) as a colorless oil:α!²³ _(D) -39.3° (c 2.01, CHCl₃); IR (CHCl₃) 3015 (m), 2960 (s), 2940(s), 2860 (m), 1620 (w), 1520 (m), 1465 (m), 1430 (w), 1390 (m), 1305(w), 1255 (s), 1230 (m), 1215 (m), 1205 (m), 1170 (m), 1120 (m), 1070(m), 1035 (m), 990 (w), 970 (w), 930 (w), 830 (m) cm⁻¹ ; ¹ H NMR (500MHZ, CDCl₃) d 7.39 (d, J=8.7 Hz, 2 H), 6.86 (d, J=8.8 Hz, 2 H), 5.40 (s,1 H), 4.09 (dd, J=11.2, 4.7 Hz, 1 H), 3.85 (dd, J=7.1, 1.9 Hz, 1 H),3.79 (s, 3 H), 3.48 (dd, J=8.2, 1.5 Hz, 1 H), 3.47 (apparent t, J=11.1Hz, 1 H), 3.18-3.12 (m, 2 H), 2.11-2.00 (m, 2 H), 1.84 (ddq, J=7.1, 7.1,1.6 Hz, 1 H), 1.02 (d, J=7.1 Hz, 3 H), 0.98 (d, J=6.7 Hz, 3 H), 0.89 (s,9 H), 0.72 (d, J=6.7 Hz, 3 H), 0.06 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃)d 159.8, 131.4, 127.4, 113.4, 100.9, 82.4, 75.5, 73.2, 55.3, 39.6, 38.7,30.7, 26.2, 18.4, 14.7, 14.5, 12.2, 10.7, -3.7, -3.8; high resolutionmass spectrum (CI, NH₃) m/z 548.1833 (M)⁺ ; calcd for C₂₄ H₄₁ O₄ Si:548.1819!.

Anal. Calcd for C₂₄ H₄₁ O₄ ISi: C, 52.55; H, 7.53. Found: C, 52.77; H,7.68.

EXAMPLE 11 Amide (+)-17

A solution of common precursor (+)-5 (12.1 g, 37.2 mmol) and2,6-lutidine (7.80 mL, 70.0 mmol) in CH₂ Cl₂ (90 mL) was cooled to 0° C.and tert-Butyldimethylsilyl trifluoromethanesulfonate (12.8 mL, 55.8mmol) was added over 10 min. After 1.5 h, the mixture was diluted withEt₂ O (100 mL), washed with aqueous NaHSO₄ (1.0M), brine (200 mL each),dried over MgSO₄, filtered and concentrated. Flash chromatography (10%ethyl acetate/hexanes) provided (+)-17 (16.4 g, 100% yield) as acolorless oil: !²³ _(D) +9.49° (c 1.47, CHCl₃); IR (CHCl₃) 3018 (s),2970 (s), 2945 (3), 2900 (m), 2870 (s), 1658 (s), 1620 (m), 1592 (w),1520 (s), 1470 (s), 1448 (m), 1425 (m), 1393 (m), 1367 (m), 1308 (m),1255 (w), 1213 (s), 1185 (m), 1178 (m), 1115 (s), 1084 (s), 1042 (2),1000 (e), 940 (w), 928 (w), 871 (s), 839 (s), 770 (s), 726 (s), 664 (m)cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.21 (d, J=8.7 Hz, 2 H), 6.83 (d,J=8.7, 2 H), 4.36 (ABq, J_(AB) =11.6 Hz, Δδ_(AB) =17.3 Hz, 2 H), 3.(92(dd, J )8.62, 3.0 Hz, 1 H), 3.77 (s, 3 H), 3.55 (s, 3 H), 3.54 (dd,J=9.2, 2.5 Hz, 1 H), 3.13 (dd, J=9.2, 7.8 Hz, 1 H), 3.09 (s, 3 H),3.15-3.09 (m, 1 H), 1.92-1.87 (m, 1 H), 1.09 (d, J=7.0 Hz, 3 H), 0.98(d, J 7.0 Hz, 3 H), 0.88 (s, 9 H)(0.04 (apparent s, 6 H); ¹³ C NMR (125MHZ, CDCl₃) d 176.8, 159.1, 130.9, 12 9.2, 113.7, 76.0, 72.7, 71.9,61.1, 55.2, 39.3, 38.9, 26.1, 18.4, 15.3, 15.0, -3.87, -3.93; highresolution mass spectrum (CI, NH₃) m/z 440.2823 (M+H)⁺ ; calcd for C₂₅H₄₂ NO₅ Si: 440.2832!.

Anal. Calcd for C₂₃ H₄₁ NO₅ Si: C, 62.83; H, 9.40. Found: C, 63.05; H,9.32.

EXAMPLE 12 Aldehyde (+)-18

A solution of amide (+)-17 (9.19 g, 20.9 mmol) in THF (350 mL) wascooled to -78° C. and DIBAL (1.0M in hexane, 44.0 mL, 44.0 mmol) wasadded over 30 min. After 0.5 h at -78° C., the reaction was quenchedwith MeOH (10 mL). The mixture was diluted with ether (500 mL), washedwith saturated aqueous Rochelle's salt, brine (300 mL each), dried overMgSO₄, filtered and concentrated. Flash chromatography (10% ethylacetate/hexane) gave (+)-18 (7.05 g, 89% yield) as a colorless oil: α!²³_(D) +23.2° (c 1.49, CHCl₃); IR (CHCl₃) 2960 (s), 2930 (s), 2860 (s),1730 (s), 1610 (m), 1583 (w), 1510 (m), 1460 (m), 1373 (m), 1360 (w),1300 (m), 1245 (s), 1170 (m), 1085 (m), 1033 (s), 933 (w), 835 (s) cm⁻¹; ¹ H NMR (500 MHZ, CDCl₃) d 9.67 (d, J=0.9 Hz, 1 H), 7.22 (d, J=8.7 Hz,2 H), 6.86 (d, J=8.7 Hz, 2 H), 4.37 (ABq, J_(AB) =11.6 Hz, Ad6A=23.6 Hz,2 H), 4.18 (dd, J=6.1, 3.7 Hz, 1 H), 3.78 (s, 3 H), 3.41 (dd, J=9.2, 5.7Hz, 1 H), 3.31 (dd, J=9.2, 6.0 Hz, 1 H), 2.47 (qdd, J=7.1, 3.7, 0.9 Hz,1 H), 2.03-1.95 (m, 1 H), 1.08 (d, J=7.0 Hz, 3 H), 0.94 (d, J=7.0 Hz, 3H), 0.84 (s, 9 H), 0.04 (s, 3 H), -0.03 (s, 3 H); ¹³ C NMR (125 MHZ,CDCl₃) d 204.8, 159.2, 130.5, 129.2, 113.8, 72.7, 72.4, 71.7, 55.3,50.0, 38.3, 25.9, 18.2, 14.3, 8.4, -4.1, -4.4; high resolution massspectrum (FAB, NBA) m/z 403.2304 (M+Na)⁺ ; calcd for C₂₁ H₃₆ O₄ SiNa:403.2280!.

EXAMPLE 13 Bromo Ester 19

A solution of aldehyde (+)-18 (822.1 mg, 2.16 mmol) in benzene (20 mL)was treated with Ph₃ P═CBrCO₂ Et (2.28 g, 5.34 mmol), heated at refluxfor 40 h and cooled to room temperature. The mixture was filteredthrough a short silica column (20% ethyl acetate/hexane) andconcentrated. Flash chromatography (30 ethyl acetate/hexane) affordedZ-Bromo ester (-)-19 (861.4 mg, 75% yield) and E-Bromo Ester (+)-19(101.0 mg, 8.8% yield).

Z-Bromo Ester (-)-19: Colorless oil; α!²³ _(D) -6.38° (c 1.85, CHCl₃);IR (CHCl₃) 2960 (s), 2940 (s), 2860 (s), 1725 (s), 1618 (m), 1590 (w),1515 (s), 1468 (m), 1390 (m), 1370 (m), 1303 (m), 1250 (s, br), 1176(m), 1090 (s), 1037 (s), 1008 (m), 950 (m), 940 (m), 840 (s) cm⁻¹ ; ¹ HNMR (500 MHZ, C₆ D6) d 7.45 (d, J=9.7 Hz, 1 H), 7.26 (d, J=8.6 Hz, 2 H),6.80 (d, J=8.7 Hz, 2 H), 4.37 (ABq, J_(AB) =11.6 Hz, Δδ_(AB) =19.3 Hz, 2H), 3.99, (dq, J=10.8, 7.1 Hz, 1 H), 3.94 (dq, J=10.8, 7.1 Hz, 1 H),3.82 (apparent t, J=5.4 Hz, 1 H), 3.41 (dd, J=9.1, 6.3 Hz, 1 H), 3.31(s, 3 H), 3.30 (dd, J=9.2, 6.5 Hz, 1 H), 3.13-3.06 (m, 1 H), 2.05(apparent septet, J=6.9 Hz, 1 H), 1.013 (d, J=7.0 Hz, 3 H), 1.006 (d,J=6.8 Hz, 3 H), 0.97 (s, 9 H), 0.92 (apparent t, J=7.1 Hz, 3 H), 0.06(s, 3 H), 0.05 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 162.5, 159.1,149.6, 130.8, 129.0, 114.9, 113.7, 75.5, 72.6, 72.2, 62.4, 55.3, 40.2,38.9, 26.0, 18.3, 14.2, 14.1, 13.7, -4.0, -4.2; high resolution massspectrum (CI, NH₃) m/z 546.2270 (M+NH)⁺ ; calcd for C₂₅ H₄₅ NO₅ BrSi:546.2251!.

Anal. Calcd for C₂₅ H₄₁ O₅ BrSi: C, 56.70; H, 7.80. Found: C, 56.96; H,7.86.

E-Bromo Ester (+)-19. Colorless oil; α!²³ _(D) +3.2° (c 1.65, CHCl₃); IR(CHCl₃) 2965 (s), 2940 (s), 2905 (m), 2890 (m), 2865 (s), 1720 (s), 1617(m), 1590 (w), 1518 (s), 1468 (s), 1375 (s), 1350 (m), 1305 (m), 1250(s, br), 1177 (m), 1090 (s), 1035 (s), 1007 (m), 950 (m), 840 (s), 675(w) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.23 (d, J=8.6 Hz, 2 H), 6.86 (d,J=8.7 Hz, 2 H), 6.56 (d, J=10.6 Hz, 1 H), 4.39 (apparent s, 2 H), 4.24(dq, J=10.8, 7.1 Hz, 1 H), 4.22 (dq, J=10.8, 7.1 Hz, 1 H), 3.79 (s, 3H), 3.61 (dd, J=5.5, 5.0 Hz, 1 H), 3.43 (dd, J=9.2, 5.5 Hz, 1 H),3.39-3.32 (m, 1 H), 3.24 (dd, J=9.1, 7.2 Hz, 1 H), 1.98-1.90 (m, 1 H),1.30 (apparent t, J=7.1 Hz, 1 H), 1.00 (d, J=6.7 Hz, 3 H), 0.94 (d,J=7.0 Hz, 3 H), 0.89 (s, 9 H), 0.05 (s, 3 H), 0.03 (s, 3 H); ¹³ C NMR(125 MHZ, CDCl₃) d 162.8, 159.1, 151.9, 130.8, 129.1, 113.7, 110.2,76.3, 72.6, 72.2, 62.1, 55.2, 38.8, 26.1, 18.3, 14.7, 14.1, 13.9, -4.06,-4.10; high resolution mass spectrum (CI, NH₃) m/z 529.1982 (M+H)⁺ ;calcd for C₂₅ H₄₂ BrO₅ Si: 529.1985!.

Anal. Calcd for C₂₅ H₄₁ O₅ BrSi: C, 56.70; H, 7.80. Found: C, 56.83; H,7.99.

EXAMPLE 14 Allylic Alcohol (-)-20

A solution of ester (-)-19 (858.4 mg, 1.62 mmol) in CH₂ Cl₂ (16 mL) wascooled to -78° C. and DIBAL (1.0M in hexane, 3.60 mL, 3.60 mmol) wasadded over 10 min. After 5 min at -78° C. and 10 min at roomtemperature, the reaction was quenched with MeOH (200 mL), followed byaddition of saturated aqueous Rochelle's salt dropwise with stirringuntil a solid precipitated. The solution was separated by decanting(3×30 mL rinse, ethyl acetate) and the combined organic solutions weredried over MgSO₄, and concentrated. Flash chromatography (10% ethylacetate/hexane) provided (-)-20 (674.5 mg, 85% yield) as a colorlessoil: α!²³ _(D) -15.5° (c 2.51, CHCl₃); IR (CHCl₃) 3600 (w), 3420 (w,br), 3010 (m), 2960 (s), 2940 (s), 2890 (m), 2860 (s), 1618 (m), 1590(w), 1520 (s), 1470 (m), 1380 (m), 1315 (m), 1307 (m), 1255 (s), 1178(m), 1085 (s), 1039 (s), 1010 (m), 972 (m), 940 (m), 840 (s), 675 (m),660 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.24 (d, J=8.7 Hz, 2 H), 6.87(d, J=8.7 Hz, 2 H), 5.88 (br d, J=9.3 Hz, 1 H), 4.39 (ABq, J_(AB) =11.6Hz, Δδ_(AB) =18.3 Hz, 2 H), 4.16 (apparent d, J=5.6 Hz, 2 H), 3.79 (s, 3H), 3.59 (apparent t, J=5.3 Hz, 1 H), 3.48 (dd, J=9.2, 5.3 Hz, 1 H),3.23 (dd, J=9.2, 7.7 Hz, 1 H), 2.82-2.76 (m, 1 H), 2.00-1.92 (m, 1 H),0.98 (d, J=6.9 Hz, 3 H), 0.97 (d, J=6.8 Hz, 3 H), 0.88 (s, 9 H), 0.024(s, 3 H), 0.016 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 159.1, 134.1,130.9, 129.1, 125.1, 113.7, 76.5, 72.6, 72.3, 68.4, 55.3, 39.1, 38.7,26.1, 18.4, 14.9, 14.3, -3.9, -4.0; high resolution mass spectrum (CI,NH₃) m/z 487.1873 (M+H)⁺ ; calcd for C₂₃ H₄₀ O₄ BrSi: 487.1879!.

Anal. Calcd for C₂₃ H₃₉ O₄ BrSi: C, 56.66; H, 8.06. Found: C, 56.72; H,8.07.

EXAMPLE 15 Mesylate (-)-21

A solution of alcohol (-)-20 (6.85 g, 14.1 mmol) in CH₂ Cl₂ (150 mL) wascooled to 0° C. and MsCl (2.20 mL, 28.4 mmol) was added over 2 min.After 10 min, the reaction was quenched with aqueous NaHSO₄ (1.0M, 100mL). The organic phase was washed with water (100 mL), dried over MgSO₄,and concentrated. Flash chromatography (10% ethyl acetate/hexane)afforded (-)-21 (7.85 g, 99i yield) as a colorless oil: α!²³ _(D) -14.6°(c 1.40, CHCl₃); IR (CHCl₃) 3020 (m), 2960 (s), 2940 (s), 2880 (m), 2860(s), 1730 (w), 1610 (m), 1583 (m), 1510 (s), 1460 (m), 1410 (m), 1362(s), 1300 (m), 1250 (s), 1220 (s), 1175 (s), 1080 (s), 1032 (s), 1002(m), 960 (m), 937 (s), 835 (s) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.23(d, J=8.6 Hz, 2 H), 6.86 (d, J=8.6 Hz, 2 H), 6.07 (d, J=9.4 Hz, 1 H),4.74 (d, J=0.4 Hz, 2 H), 4.38 (ABq, J_(AB) =11.7 Hz, Δδ_(AB) =25.5 Hz, 2H), 3.79 (s, 3 H), 3.61 (apparent t, J=5.2 Hz, 1 H), 3.44 (dd, J=9.2,5.7 Hz, 1 H), 3.22 (dd, J=9.2, 7.3 Hz, 1 H), 3.01 (s, 3 H), 2.84-2.77(m, 1 H), 1.99-1.91 (m, 1 H), 0.98 (d, J=6.8 Hz, 3 H), 0.96 (d, J=7.0Hz, 3 H), 0.88 (s, 9 H), 0.03 (s, 3 H), 0.02 (s, 3 H); ¹³ C NMR (125MHZ, CDCl₃) d 159.1, 140.9, 130.8, 129.1, 116.7, 113.8, 76.1, 74.2,72.6, 72.1, 55.3, 39.6, 38.8, 38.5, 26.0, 18.3, 14.7, 14.3, -3.9, -4.0;high resolution mass spectrum (CI, NH₃) m/z 582.1911 (M+NH )⁺ ; calcdfor C₂₄ H₄₅ NO₆ BrSSi: 582.1920!.

EXAMPLE 16 Vinyl Bromide (-)-22

A solution of mesylate (-)-21 (6.43 g, 11.4 mmol) in benzene (120 mL)was treated with LiBHEt: (1.0M in THF, 25.0 mL, 25.0 mmol) at roomtemperature. After 0.5 h, the reaction was quenched with aqueous NaOH(1.0N, 50 mL). The mixture was diluted with ethyl acetate (200 mL),washed with brine (2×200 mL), dried over MgSO₄, filtered andconcentrated. Flash chromatography (5% ethyl acetate/hexane) provided(-)-22 (4.86 g, 91%) as a colorless oil: α!²³ _(D) -16.9° (c 1.69,CHCl₃); IR (CHCl₃) 3005 (m), 2965 (s), 2935 (s), 2860 (s), 1660 (w),1610 (m), 1585 (w), 1510 (m), 1460 (m), 1425 (w), 1377 (m), 1360 (m),1300 (m), 1250 (s), 1180 (m), 1170 (m), 1075 (s), 1030 (m), 860 (m), 835(s), 805 (m), 660 (w) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.24 (d, J=8.6Hz, 2 H), 6.86 (d, J=8.6 Hz, 2 H), 5.47 (apparent dd, J=9.0, 1.2 Hz, 1H), 4.39 (ABq, JAB=11.7 Hz, Δδ_(AB) =15.8 Hz, 2 H), 3.79 (s, 3 H), 3.56(apparent t, J=5.4 Hz, 1 H), 3.50 (dd, J=9.1, 5.1 Hz, 1 H), 3.22 (dd,J=8.8, 8.1 Hz, 1 H), 2.74-2.67 (m, 1 H), 2.21 (d, J=1.1 Hz, 3 H),1.99-1.91 (m, 1 H), 0.98 (d, J=6.9 Hz, 3 H), 0.94 (d, J=6.8 Hz, 3 H),0.88 (s, 9 H), 0.01 (s, 3 H), 0.00 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d159.1, 133.4, 131.0, 129.1, 120.6, 113.7, 76.7, 72.6, 72.5, 55.3, 39.7,38.7, 28.8, 26.1, 18.4, 14.8, 14.4, -3.96, -4.01; high resolution massspectrum (FAB, NBA) m/z 493.1763 (M+Na)⁺ ; calcd for C₂₃ H₃₉ O₃ BrSiNa:493.1750!.

EXAMPLE 17 Vinyl Silane (-)-23

A solution of vinyl bromide (-)-22 (83.2 mg, 0.177 mmol) in THF (2.0 mL)was cooled to -78° C. and n-BuLi (1.6M in hexane, 260 ml, 416 mmol) wasadded over 10 min. After 1 h at -78° C. and 15 min at room temperature,the reaction was quenched with H₂ O (200 mL). The mixture wasconcentrated and dissolved in ethyl acetate (30 mL), washed with water(30 mL), dried over MgSO₄, filtered and concentrated. Flashchromatography (5% ethyl acetate/hexane) provided (-)-23 (47.9 mg, 69%yield) as a colorless oil: α!²³ _(D) -61.5° (c 0.615, CHCl₃); IR (CHCl₃)3680 (w), 3470 (m, br), 1614 (m), 1588 (w), 1513 (s), 1465 (m), 1442(m), 1415 (m), 1360 (m), 1302 (m), 1250 (s), 1176 (m), 1120 (m), 1077(m), 1032 (m), 992 (m), 830 (s), 820 (s), 805 (s) cm⁻¹ ; ¹ H NMR (500MHZ, CDCl₃) d 7.22 (d, J=8.7 Hz, 2 H), 6.85 (d, J=8.7 Hz, 2 H), 6.22(dq, J=10.5, 1.6 Hz, 1 H), 4.42 (ABq, J_(AB) =11.4 Hz, Δδ_(AB) =18.8 Hz,2 H), 3.78 (s, 3 H), 3.65 (br s, 1 H), 3.56 (dd, J=9.1, 4.0 Hz, 1 H),3.44 (dd, J=8.8, 2.9 Hz, 1 H), 3.42 (apparent t, J=8.8 Hz, 1 H), 2.45(dqd, J=10.3, 6.6, 2.7 Hz, 1 H), 1.95-1.87 (m, 1 H), 1.78 (d, J=1.6 Hz,3 H), 0.91 (d, J=6.7 Hz, 3 H), 0.87 (s, 9 H), 0.80 (d, J=7.0 Hz, 3 H),0.09 (s, 3 H), 0.08 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 159.4, 147.7,130.8, 129.7, 129.4, 113.9, 79.9, 76.4, 73.3, 55.3, 38.1, 36.3, 27.1,26.6, 17.8, 13.4, 13.1, -3.4, -3.7; high resolution mass spectrum (CI,NH₃) m/z 393.2821 (M+H)⁺ ; calcd for C₂₃ H₄₁ O₃ Si: 393.2824!.

Anal. Calcd for C₂₃ H₄₀ O₃ Si: C, 70.36; H, 10.27. Found: C, 70.58; H,10.57.

EXAMPLE 18 trans Olefin (+)-24

A solution of vinyl bromide (-)-22 (27.8 mg, 0.0591 mmol) in ether (600μL) was cooled to -78° C., and t-BuLi (1.7 M in pentane, 103 μL, 0.175mmol) was added over 2 min. After 10 min at -78° C. and 5 min at roomtemperature, the reaction was quenched with MeOH (100 mL). The mixturewas filtered through a short silica plug, and concentrated. Flashchromatography (1% ethyl acetate/hexane) provided (+)-24 (21.9 mg, 94%yield) as a colorless oil; α!²³ _(D) +19.3° (C 1.10, CHCl₃); IR (CHCl₃)3000 (m), 2960 (s), 2935 (s), 2880 (m), 2860 (s), 1612 (m), 1587 (w),1510 (s), 1462 (m), 1440 (m), 1405 (w), 1375 (m), 1360 (m), 1300 (m),1250 (s), 1170 (m), 1090 (s), 1034 (s), 1002 (m), 970 (m), 934 (w), 850(m), 832 (s), 720 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, C₆ D₆) d 7.24 (d, J=8.7Hz, 2 H), 6.80 (d, J=8.6 Hz, 2 H), 5.43 (ddq, J=15.3, 7.8, 1.4 Hz, 1 H),5.34 (dqd, J=15.4, 6.3, 0.7 Hz, 1 H), 4.38 (ABq, J_(AB) =11.7 Hz,Δδ_(AB) =30.7 Hz, 2 H), 3.58 (apparent t, J=5.2 Hz, 1 H), 3.57 (dd,J=9.0, 5.1 Hz, 1 H), 3.36 (dd, J=9.0, 7.2 Hz, 1 H), 3.30 (s, 3 H), 2.39(ddq, J=6.8, 6.8, 6.8 Hz, 1 H), 2.17-2.10 (m, 1 H), 1.58 (apparent d,J=6.1 Hz, 3 H), 1.07 (d, J=7.2 Hz, 3 H), 1.05 (d, J=6.9 Hz, 3 H), 1.00(s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d159.0, 135.6, 131.1, 129.1, 123.9, 113.7, 78.4, 72.6, 72.5, 55.3, 40.4,37.9, 26.2, 26.1, 18.4, 18.0, 15.9, 15.1, -3.8, -4.1; high resolutionmass spectrum (CI, NH₃) m/z 393.2836 (M+H)⁺ ; calcd for C₂₃ H₄₁ O₃ Si:393.2824!.

EXAMPLE 19 Alcohol (-)-25

A solution of PMB ether (-)-22 (50.0 mg, 0.106 mmol) and PMB acetal(-)-15 (46.5 mg, 0.106 mmol) in CH₂ Cl₂ (2.0 mL) was cooled to 0° C.,then treated with H₂ O (100 mL) and DDQ (26.5 mg, 0.117 mmol). After 30min, the mixture was diluted with ether (60 mL), washed with saturatedaqueous NaHCO₃ (60 mL), brine (3×60 mL), dried over MgSO₄, filtered andconcentrated. Flash chromatography (gradient elution, 5%→10% ethylacetate/hexane) afforded (-)-25 (31.0 mg, 83% yield) and recovered(-)-15 (40.0 mg, 86% recovery).

(-)-25: α!²³ _(D) -13.3° (c 0.99, CHCl₃); IR (CHCl₃) 3640 (w), 3520 (m),3000 (m), 2960 (s), 2940 (s), 2890 (m), 2860 (s), 1660 (w), 1472 (m),1465 (m), 1440 (m), 1407 (m), 1390 (m), 1380 (m), 1360 (m), 1258 (s),1072 (s), 1023 (s), 1005 (s), 980 (m), 937 (m), 847 (s) cm⁻¹ ; ¹ H NMR(500 MHZ, CDCl₃) d 5.50 (apparent dd, J=9.0, 1.1 Hz, 1 H), 3.65 (dd,J=11.0, 4.8 Hz, 1 H), 3.59 (dd, J=11.0, 5.7 Hz, 1 H), 3.56 (apparent t,J=5.2 Hz, 1 H), 2.80-2.72 (m, 1 H), 2.25 (d, J=1.0 Hz, 3 H), 2.20 (br s,1 H), 1.86-1.78 (m, 1 H), 0.99 (d, J=7.1 Hz, 3 H), 0.98 (d, J=6.9 Hz, 3H), 0.90 (s, 9 H), 0.09 (s, 3 H), 0.05 (s, 3 H); ¹³ C NMR (125 MHZ,CDCl₃) d 132.6, 121.7, 79.7, 65.6, 40.9, 38.8, 28.9, 26.1, 18.3, 15.5,15.0, -3.9, -4.0; high resolution mass spectrum (CI, NH₃) m/z 351.1087M⁺ ; calcd for C₁₅ H₃₁ O₂ BrSi: 351.1093!.

EXAMPLE 20 Alcohol (+)-26

A solution of amide (+)-17 (323.5 mg, 0.738 mmol) in EtOH (8.0 mL) wasstirred for 5 h under H₂ atmosphere in the presence of Pearlman'scatalyst (20% Pd(OH)₂ /C, 104.1 mg), then filtered and concentrated.Flash chromatography (10 mL silica, 20% ethyl acetate/hexane) provided(+)-26 (216.7 mg, 92% yield) as a colorless oil: α!²³ _(D) +16.1° (c2.60, CHCl₃); IR (CHCl₃) 3480 (m, br), 3000 (s), 2958 (s), 2935 (s),2880 (s), 2860 (s) 1635 (s), 1460 (s), 1415 (m), 1390 (s), 1360 (m),1285 (w) 1255 (s), 1174 (m), 1148 (m), 1093 (s), 1070 (s), 1047 (s) 1033(s), 990 (s), 935 (m), 905 (w), 860 (s), 830 (s) cm⁻¹ ; ¹ H NMR (500MHZ, CDCl₃) d 4.05 (dd, J=9.1, 3.1 Hz, 1 H), 3.69 (s, 3 H), 3.55-3.50(m, 1 H), 3.23 (ddd, J=10.1, 10.1, 2.8 Hz, 1 H), 3.13 (s, 3 H), 3.09 (brm, 1 H), 2.81 (br m, 1 H), 1.91-1.83 (m, 1 H), 1.14 (d, J=7.0 Hz, 3 H),0.879 (d, J=7.0 Hz, 3 H), 0.879 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H);¹³ C NMR (125 MHZ, CDCl₃) d 177.3, 75.2, 64.9, 61.5, 40.8, 38.2, 32.2,26.0, 18.2, 15.9, 12.8, -4.1, -4.3; high resolution mass spectrum (CI,NH₃) m/z 320.2265 (M+H)⁺ ; calcd for C₁₅ H₃₄ NO₄ Si: 320.2256!.

EXAMPLE 21 Aldehyde (+)-27

A solution of alcohol (+)-26 (8.80 g, 27.5 mmol) and NEt3 (15.3 mL, 110mmol) in CH₂ Cl₂ (50 mL) was cooled to -10° C. and treated with SO₃.pyr(13.1 g, 82.6 mmol) in DMSO (100 mL). After 20 min at room temperature,the mixture was diluted with ether (300 mL), washed with aqueous NaHSO₄(1.0M, 200 mL), brine (4×200 mL), dried over MgSO₄, filtered andconcentrated. Flash chromatography (20% ethyl acetate/hexane) afforded(+)-27 (8.55 g, 98% yield) as a colorless oil: α!₂₃ ^(D) +51.2° (c 1.00,CHCl₃); IR (CHCl) 3010 (m), 2960 (s), 2940 (s), 2895 (m), 2865 (m), 1750(m), 1720 (s), 1647 (s), 1460 (s), 1420 (m), 1390 (s), 1360 (m), 1255(s), 1180 (m), 1105 (m), 1077 (m), 1040 (s), 995 (s), 936 (m), 853 (s),837 (s), 710 (m), 657 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 9.68 (d,J=1.6 Hz, 1 H), 4.22 (dd, J=8.9, 2.6 Hz, 1 H), 3.68 (s, 3 H), 3.10(apparent s, 4 H), 2.46 (qdd, J=7.1, 2.6, 1.5 Hz, 1 H), 1.16 (d, J=6.9Hz, 3 H), 1.10 (d, J=7.0 Hz, 3 H), 0.88 (s, 9 H), 0.092 (s, 3 H), 0.088(s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 203.2, 175.6, 75.1, 61.5, 52.1,39.6, 32.1, 25.9, 18.2, 15.4, 10.2, -4.07, -4.11; high resolution massspectrum (CI,NH₃) m/z 318.2096 (M+H)⁺ ; C₁₅ H₃₂ NO₄ Si: 318.2100!.

EXAMPLE 22 Dithiane (+)-28

A solution of ZnCl₂ (dried at 140° C. for 1 h under vacuum, 170.5 mg,1.25 mmol) in ether (6.0 mL) was cooled to 0° C. and (TMSSCH₂)₂ CH₂(175.0 μL, 0.628 mmol) was added. The resultant white milky suspensionwas treated with aldehyde (+)-27 (180.0 mg, 0.567 mmol) in ether (6.0mL). The mixture was stirred for 4.5 h at 0° C. and 1.5 h at roomtemperature, then partitioned between ethyl acetate (50 mL) and aqueousammonia (30 mL). The organic phase was washed with brine (2×30 mL),dried over MgSO₄, filtered and concentrated. Flash chromatography (10%ethyl acetate/hexane) provided (+)-28 (182.9 mg, 79% yield) as a whitesolid: mp 55°-57° C.; α!²³ _(D) +18.5° (c 1.44, CHCl₃); IR (CHCl₃) 3015(m), 2970 (s), 2945 (s), 2910 (m), 2870 (m), 1665 (s), 1475 (m), 1470(m), 1437 (m), 1430 (m), 1420 (m), 1390 (m), 1365 (m), 1320 (w), 1280(m), 1260 (m), 1120 (m), 1115 (m), 1097 (m), 1080 (m), 1065 (m), 1040(m), 1000 (m), 940 (w), 925 (w), 910 (w), 877 (m), 838 (s), 815 (m), 800(m), 700 (w), 675 (w), 660 (w) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 4.33(d, J=4.2 Hz, 1 H), 4.23 (dd, J=7.1, 3.6 Hz, 1 H), 3.68 (s, 3 H), 3.15(s, 3 H), 2.98 (dq, J 6.8, 3.7 Hz, 1 H), 2.90 (ddd, J=14.1, 12.2, 2.5Hz, 1 H), 2.83-2.77 (m, 3 H), 2.09-2.03 (m, 1 H), 1.94 (ddq, J=7.2, 7.2,4.3 Hz, 1 H), 1.88-1.76 (m, 1 H), 1.08 (d, J=7.2 Hz, 3 H), 1.07 (d,J=6.9 Hz, 3 H), 0.90 (s, 9 H), 0.13 (s, 3 H), 0.02 (s, 3 H); ¹³ C NMR(125 MHZ, CDCl₃) d 176.2, 73.2, 61.0, 50.8, 44.2, 38.6, 31.3, 30.3,26.2, 18.4, 12.9, 11.0, -4.1, -4.2; high resolution mass spectrum (CI,NH₃) m/z 408.2081 (M+H)⁺ ; calcd for C₁₈ H₃₈ NO₃ S₂ Si: 408.2062!.

Anal. Calcd. for C₁₈ H₃₇ NO₃ S₂ Si: C, 53.03; H, 9.15. Found: C, 53.06;H, 9.31.

EXAMPLE 23 Aldehyde (+)-29

A solution of dithiane (+)-28 (1.05 g, 2.58 mmol) in THF (40 mL) wascooled to -78° C. and DIBAL (1.0M in hexane, 5.15 mL, 5.15 mmol) wasadded over 15 min. After 10 min at -78° C., the mixture was quenchedwith MeOH (2.0 mL) and partitioned between ether and saturated aqueousRochelle's salt (50 mL each). The organic phase was washed with brine(30 mL), dried over MgSO₄, filtered and concentrated. Flashchromatography (10% ethyl acetate/hexane) provided (+)-29 (822 mg, 91%yield) as white solid: mp 54°-55° C.; α!²³ _(D) +50.8° (c 1.19, CHCl₃);IR (CHCl₃) 2965 (s), 2940 (s), 2910 (s), 2865 (s), 2720 (w), 1730 (s),1475 (m), 1467 (m), 1428 (m), 1418 (m), 1390 (m), 1365 (m), 1280 (m),1260 (s), 1190 (m), 1150 (m), 1104 (s), 1070 (m), 1030 (s), 1007 (m),953 (m), 940 (m), 910 (m), 835 (s), 810 (m), 675 (m) cm⁻¹ ; ¹ H NMR (500MHZ, CDCl₃) d 9.70 (s, 1 H), 4.44 (dd, J=8.3, 2.2 Hz, 1 H), 4.38 (d,J=3.7 Hz, 1 H), 2.93 (ddd, J=14.1, 12.3, 2.6 Hz, 1 H), 2.84-2.80 (m, 3H), 2.43 (qd, J=7.1, 2.2 Hz, 1 H), 2.13-2.07 (m, 1 H), 2.02 (dqd, J=8.2,7.1, 3.7 Hz, 1 H), 1.88-1.79 (m, 1 H), 1.10 (d, J=6.9 Hz, 3 H), 1.05 (d,J=7.1 Hz, 3 H), 0.87 (s, 9 H), 0.16 (s, 3 H), -0.01 (s, 3 H); ¹³ C NMR(125 MHZ, CDCl₃) d 204.6, 71.1, 51.0, 49.7, 43.5, 31.3, 30.3, 26.2,26.0, 18.4, 12.9, 6.8, -3.9, -4.3; high resolution mass spectrum (CI,NH₃) m/z 349.1678 (M+H)⁺ ; calcd for C₁₆ H₃₃ O₂ S₂ Si: 349.1691!.

Anal. Calcd for C₁₆ H₃₂ O₂ S₂ Si: C, 55.12; H, 9.25. Found: C, 55.08; H,9.28.

EXAMPLE 24 Dimethoxy Acetal (+)-30

A solution of aldehyde (+)-29 (792 mg, 2.27mmol) in HC(OMe)₃ /MeOH (48mL, 1:5) was treated with TsOH.H₂ O (8.6 mg, 0.045 mmol) at roomtemperature. After 30 min, NEt₃ (1.0 mL) was added and the mixture wasconcentrated. Flash chromatography (10% ethyl acetate/hexane) provided(+)-30 (886 mg, 99% yield) as a white solid: mp 58°-59° C.; α!²³ _(D)+27.1° (c 2.85, CHCl₃); IR (CHCl₃) 2960 (s), 2940 (s), 2905 (s), 2860(m), 2835 (m), 1473 (m), 1463 (m), 1432 (m), 1425 (m), 1415 (m), 1387(m), 1362 (m), 1340 (w), 1278 (m), 1252 (s), 1190 (m), 1158 (m), 1104(s), 1070 (m), 1050 (m), 1030 (s), 1005 (m), 963 (m), 938 (m), 908 (m),873 (m), 834 (s), 810 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 4.41 (d,J=3.1 Hz, 1 H), 4.23 (d, J=8.6 Hz, 1 H), 4.02 (dd, J=8.6, 1.3 Hz, 1 H),3.29 (s, 3 H), 3.26 (s, 3 H), 2.93 (ddd, J=14.0, 12.4, 2.5 Hz, 1 H),2.85-2.78 (m, 3 H), 2.11-2.05 (m, 1 H), 1.93-1.77 (m, 3 H), 1.00 (d,J=7.2 Hz, 3 H), 0.91 (s, 9 H), 0.85 (d, J=6.9 Hz, 3 H), 0.17 (s, 3 H),0.09 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 105.0, 71.5, 53.0, 51.5,51.2, 43.8, 37.4, 31.3, 30.2, 26.3, 18.8, 12.9, 8.1, -3.8, -4.3; highresolution mass spectrum (FAB, NBA) m/z 417.1934 (M+Na)⁺ ; calcd for C₁₈H₃₈ O₃ S₂ SiNa: 417.1930!.

Anal. Calcd for C₁₈ H₃₈ O₃ S₂ Si: C, 54.78; H, 9.70. Found: C, 54.80; H,9.66.

EXAMPLE 25 Hydroxy Acetal (-)-32

A solution of dithiane (+)-30 (3.60 g, 9.12 mmol) in 10% HMPA/THF (60mL) was cooled to -78° C. and treated with t-BuLi (1.7M in pentane, 5.63mL, 9.58 mmol) dropwise over 15 min. The mixture was stirred 1 h at -78°C. and 1 h at -42° C., then recooled to -78° C. A solution of benzylR-(-)-glycidyl ether (1.65 g, 10.0 mmol) in 100 HMPA/THF (12 mL) wasadded via cannula. After 0.5 h, the reaction mixture was warmed to -42°C. for 0.5 h and quenched with saturated aqueous NH₄ Cl (20 mL). Themixture was diluted with ether (200 mL), washed with water, brine (200mL each), dried over MgSO₄, filtered and concentrated. Flashchromatography (10% ethyl acetate/hexane) afforded (-)-32 (4.04 g, 79%yield) as a colorless oil: α!²³ _(D) -5.9° (c 2.1, CHCl₃); IR (CHCl₃)3450 (w, br), 3020 (m), 2960 (s), 2940 (s), 2910 (m), 2860 (m), 2840(m), 1605 (w), 1500 (w), 1475 (m), 1468 (m), 1458 (m), 1440 (m), 1430(m), 1393 (m), 1387 (m), 1365 (m), 1280 (w), 1255 (m), 1233 (m), 1203(m), 1167 (w), 1153 (w), 1110 (s), 1060 (m), 1045 (m), 1030 (m), 1010(m), 980 (w), 940 (m), 910 (w), 860 (m), 837 (s), 800 (m), 695 (m), 670(m), 660 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.35-7.25 (m, 5 H), 4.64(dd, J=4.0, 1.1 Hz, 1 H), 4.57 (ABq, J_(AB) =12.1 Hz, Δδ_(AB) =17.8 Hz,2 H), 4.21 (d, J=7.7 Hz, 1 H) 4.14-4.09 (m, 1 H), 3.48 (dd, J=9.5, 6.0Hz, 1 H), 3.47 (dd, J=9.6, 5.0 Hz, 1 H), 3.37 (d, J=0.7 Hz, 1 H), 3.36(s, 3 H), 3.29 (s, 3 H), 3.08 (ddd, J=14.4, 11.4, 2.9 Hz, 1 H), 2.95(ddd, J=14.4, 11.3, 3.1 Hz, 1 H), 2.71-2.64 (m, 2 H), 2.59 (dqd, J=6.7,6.7, 0.9 Hz, 1 H), 2.49 (dd, J=15.6, 7.9 Hz, 1 H), 2.30 (dq, J=4.0, 7.3Hz, 1 H), 2.27 (dd, J=15.6, 2.3 Hz, 1 H), 2.04-2.00 (m, 1 H), 1.86-1.78(m, 1 H), 1.18 (d, J=7.4 Hz, 3 H), 0.94 (d, J=6.8 Hz, 3 H), 0.90 (s, 9H), 0.08 (s, 3 H), 0.07 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 138.2,128.4, 127.6, 106.9, 74.4, 73.3, 70.0, 67.9, 55.7, 53.6, 52.6, 47.2,39.4, 38.5, 26.3, 26.1, 26.0, 25.0, 18.3, 9.8, 9.5, -3.9, -4.9; highresolution mass spectrum (FAB, NBA) m/z 581.2763 (M+Na)⁺ ; calcd for C₂₈H₅₀ O₅ S₂ SiNa: 581.2767!.

EXAMPLE 26 Ketone (+)-33

A solution of hydroxy acetal (-)-32 (3.94 g, 7.05 mmol) in H₂ O/MeOH(1:9, 75 mL) was treated with (CF C₃ O)₂ I₂ Ph (4.55 g, 10.6 mmol) at 0°C. After 5 min, the mixture was quenched with saturated NaHCO₃ (20 mL)and extracted with ether (200 mL). The organic phase was washed withbrine (200 mL), dried over MgSO₄, filtered and concentrated. Flashchromatography (20% ethyl acetate/hexane) furnished (+)-33 (2.66 g, 80%yield) as a colorless oil. α!²³ _(D) +36° (c 0.36, CHCl₃); IR (CHCl₃)3580 (w, br), 3005 (m), 2960 (s), 2930 (s), 2900 (m), 2860 (m), 1710(m), 1463 (m), 1455 (m), 1387 (m), 1362 (m), 1253 (m), 1220 (m), 1105(s), 1070 (s), 1053 (s), 1030 (s), 1002 (m), 938 (m), 866 (m), 830 (s),808 (m), 690 (m), 660 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.34-7.25(m, 5 H), 4.54 (apparent s, 2 H), 4.40-4.25 (m, 1 H), 4.23 (dd, J=7.6,1.9 Hz, 1 H), 4.19 (d, J=8.0 Hz, 1 H), 3.46 (dd, J=9.7, 4.9 Hz, 1 H),3.43 (dd, J=9.7, 5.9 Hz, 1 H), 3.27 (s, 3 H), 3.25 (s, 3 H), 3.01 (d,J=3.8 Hz, 1 H), 2.76 (dd, J=18.0, 8.7 Hz, 1 H), 2.74 (dq, J=7.1, 7.1 Hz,1 H), 2.62 (dd, J=17.9, 3.2 Hz, 1 H), 1.83 (dqd, J=8.0, 7.0, 1.9 Hz, 1H), 0.97 (d, J=7.1 Hz, 3 H), 0.88 (d, J=6.9 Hz, 3 H), 0.83 (s, 9 H),0.06 (s, 3 H), -0.05 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 213.0, 138.0,128.4, 127.71, 127.68, 105.0, 73.4, 73.3, 71.8, 66.5, 52.9, 52.6, 52.3,46.5, 37.9, 26.1, 18.4, 12.7, 8.8, -4.1, -4.8; high resolution massspectrum (FAB, NBA) m/z 491.2821 (M+Na)⁺ ; calcd for C₂₅ H₄₄ O₆ SiNa:491.2805!.

EXAMPLE 27 Diol (-)-34

A solution of Me₄ NBH(OAc)₃ (1.80 g, 6.84 mmol) in HOAc/CH₃ CN (1:1,10.0 mL) was cooled to -40° C. and ketone (+)-33 (536 mg, 1.14 mmol) inCH₃ CN (5 mL) was added. After 12 h at -20° C., the mixture was treatedwith saturated aqueous Rochelle's salt (20 mL) and extracted with CH₂Cl₂ (3×50 mL). The combined organic extracts were washed with saturatedNaHCO₃, brine (100 mL each), dried over MgSO₄, filtered andconcentrated. Flash chromatography (1:1:1, CH₂ Cl₂ /ether/hexane)provided (-)-34 (519 mg, 97% yield) as a colorless oil: α!²³ _(D) -7.78°(c 0.900, CHCl₃); IR (CHCl₃) 3680 (w), 3460 (m, br), 3015 (m), 2960 (s),2940 (s), 2900 (m), 2865 (s), 1470 (m), 1460 (m), 1390 (m), 1365 (m),1260 (m), 1230 (m), 1208 (m), 1112 (s), 1065 (s), 1030 (m), 1010 (m),942 (m), 865 (m), 838 (m), 698 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d7.33-7.30 (m, 4 H), 7.29-7.25 (m, 1 H), 4.55 (ABq, J_(AB) =12.0 Hz,Δδ_(AB) =15.7 Hz, 2 H), 4.16-4.11 (m, 1 H), 4.13 (d, J=7.8 Hz, 1 H),4.07 (dd, J=4.8, 1.6 Hz, 1 H), 3.73 (br s, 1 H), 3.68 (dddd, J=9.3, 9.3,2.4, 2.4 Hz, 1H), 3.50 (dd, J=9.6, 4.5 Hz, 1 H), 3.42 (dd, J=9.4, 7.0Hz, 1 H), 3.38 (s, 3 H), 3.29 (s, 3 H), 3.09 (d, J=4.0 Hz, 1 H), 1.90(dqd, J=7.0, 7.0, 1.5 Hz, 1 H), 1.76 (br dd, J=13.6, 8.5 Hz, 1 H), 1.68(dqd, J=9.6, 6.9, 5.0 Hz, 1 H), 1.49 (ddd, J=14.3, 9.0, 2.9 Hz, 1 H),0.894 (d, J=7.9 Hz, 3 H), 0.886 (s, 9 H), 0.80 (d, J=7.0 Hz, 3 H), 0.055(s, 3 H), 0.048 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 138.2, 128.4,127.7, 127.6, 107.3, 74.5, 73.3, 71.0, 70.9, 67.8, 55.2, 52.1, 45.9,37.3, 36.9, 25.9, 18.2, 11.6, 10.6, -4.3, -4.7; high resolution massspectrum (FAB, NBA) m/z 493.2951 (M+Na)⁺ ; calcd for C₂₅ H₄₆ O₆ SiNa:493.2962!.

EXAMPLE 28 Alcohol (-)-35

A solution of (-)-34 (123.3 mg, 0.262 mmol) in benzene (10 mL) wastreated with TsOH.H₂ O (2.0 mg, 0.0105 mmol) at room temperature. After20 min, the mixture was quenched with NEt₃ (1.0 mL) and concentrated.Flash chromatography (2% ether/CH₂ Cl₂) afforded 35 (100.1 mg, β/α=2:1,87% yield) as a colorless oil.

β Anomer (35): α!²³ _(D) -3.3° (c 2.25, CHCl₃); IR (CHCl₃) 3680 (w),3580 (w), 3490 (w), 3010 (m), 2960 (s), 2930 (s), 2880 (m), 2860 (s),1603 (w), 1525 (w), 1515 (w), 1493 (m), 1470 (m), 1460 (m), 1450 (m),1387 (m), 1360 (m), 1347 (m), 1330 (m), 1253 (s), 1225 (m), 1200 (m),1143 (m), 1110 (s), 1070 (s), 1045 (s), 1020 (s), 1015 (m), 1003 (m),985 (m), 950 (m), 870 (m), 853 (m), 833 (s), 807 (m), 800 (m), 790 (m),690 (m), 670 (m), 657 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.34-7.25(m, 5 H), 4.69 (d, J 2.4 Hz, 1 H), 4.55 (ABq, J_(AB) =12.0 Hz, Δδ_(AB)=14.6 Hz, 2 H), 4.17-4.12 (m, 1 H), 3.78 (ddd, J=9.7, 9.7, 2.5 Hz, 1 H),3.60 (apparent t, J=2.7 Hz, 1 H), 3.51 (dd, J=9.5, 4.1 Hz, 1 H), 3.42(s, 3 H), 3.39 (dd, J=9.5, 7.0 Hz, 1 H), 2.86 (d, J=3.8 Hz, 1 H), 1.88(apparent qt, J=7.1, 2.7 Hz, 1 H), 1.76 (ddd, J=14.4, 8.9, 2.6 Hz, 1 H),1.72-1.65 (m, 1 H), 1.53 (ddd, J=14.4, 9.3, 2.9 Hz, 1 H), 0.90 (d, J=8.2Hz, 3 H), 0.89 (s, 9 H), 0.78 (d, J=6.8 Hz, 3 H), 0.04 (s, 3 H), 0.02(s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 138.2, 128.4, 127.7, 101.2, 76.7,74.7, 73.3, 73.0, 67.4, 56.6, 41.1, 36.0, 34.7, 25.9, 18.1, 13.7, 9.7,-4.6, -4.9; high resolution mass spectrum (FAB, NBA) m/z 461.2693(M+Na)⁺ ; calcd for C₂₄ H₄₂ O₅ SiNa: 461.2699!.

α Anomer (35): α!²³ _(D) +48° (c 0.54, CHCl₃); IR (CHCl₃) 3670 (w), 3570(w), 3480 (w, br), 3005 (m), 2960 (s), 2930 (s), 2880 (m), 2855 (s),1600 (w), 1527 (w), 1515 (w), 1495 (w), 1460 (m), 1360 (m), 1253 (s),1225 (m), 1212 (m), 1200 (m), 1170 (m), 1148 (m), 1106 (s), 1087 (s),1048 (s), 1030 (s), 963 (m), 872 (m), 833 (s), 788 (m), 690 (m) cm⁻¹ ; ¹H NMR (500 MHZ, CDCl₃) d 7.34-7.24 (m, 5 H), 4.55 (ABq, J_(AB) =12.1 Hz,A As =14.4 Hz, 2 H), 4.30 (d, J=2.9 Hz, 1 H), 4.12-4.07 (m, 1 H), 4.01(ddd, J=9.2, 9.2, 2.7 Hz, 1 H), 3.51 (apparent t, J=4.4 Hz, 1 H), 3.50(dd, J=9.5, 4.2 Hz, 1 H), 3.39 (dd, J=9.5, 7.1 Hz, 1 H), 3.28 (s, 3 H),2.86 (d, J=3.2 Hz, 1 H), 1.85 (qdd, J=7.3, 5.2, 2.9 Hz, 1 H), 1.76 (dqd,J=9.3, 6.9, 4.0 Hz, 1 H), 1.71 (ddd, J=14.5, 9.0, 2.8 Hz, 1 H), 1.55(ddd, J=14.4, 9.2, 2.9 Hz, 1 H), 0.96 (d, J=7.3 Hz, 3 H), 0.88 (s, 9 H),0.81 (d, J=6.8 Hz, 3 H), 0.03 (s, 3 H), -0.01 (S, 3 H); ¹³ C NMR d138.2, 128.4, 127.7, 101.2, 76.7, 74.7, 73.3, 73.0, 67.4, 56.7, 41.1,36.0, 34.7, 25.9, 18.1, 13.7, 9.7, -4.6, -4.9; high resolution massspectrum (FAB, NBA) m/z 461.2715 (M+Na)⁺ ; calcd for C₂₄ H₄₂ O₅ SiNa:461.2699!.

EXAMPLE 29 Methyl Pyranoside 36

A solution of 35 (281.2 mg, β/α=2:1, 0.642 mmol) and 2,6-lutidine (224.0μL, 1.92 mmol) in CH₂ Cl₂ (6.0 mL) was cooled to 0° C. and TBSOTf (295.0μL, 1.28 mmol) was added over 5 min. After 1 h at 0° C., the mixture wasdiluted with ethyl acetate (100 mL), washed with aqueous NaHSO₄ (1.0M,50 mL), brine (100 mL), dried over MgSO₄, filtered and concentrated.Flash chromatography (5% ethyl acetate/hexane) provided 36 (344.6 mg,β/α=2:1, 97% yield) as a colorless oil.

α anomer: α!²³ _(D) +50.0° (c 1.44, CHCl₃); IR (CHCl₃) 2960 (s), 2935(s), 2885 (s), 2860 (s), 1490 (w), 1460 (m), 1388 (m), 1378 (m), 1360(m), 1250 (s), 1190 (m), 1145 (m), 1105 (s), 1085 (s), 1050 (s), 1025(s), 1002 (s), 963 (m), 934 (m), 867 (m), 833 (s), 690 (m) cm⁻¹ ; ¹ HNMR (500 MHZ, CDCl₃) d 7.32-7.25 (m, 5 H), 4.51 (ABq, J_(AB) =12.1 Hz,Δδ_(AB) =19.7 Hz, 2 H), 4.23 (d, J=4.8 Hz, 1 H), 4.03 (dddd, J=8.0, 5.3,5.3, 2.5 Hz, 1 H), 3.87 (ddd, J=9.9, 7.8, 1.8 Hz, 1 H), 3.53 (dd, J=7.2,4.8 Hz, 1 H), 3.39 (dd, J=9.8, 5.6 Hz, 1 H), 3.37 (dd, J=10.0, 5.2 Hz, 1H), 3.33 (s, 3 H), 1.79 (dqd, J=7.1, 7.1, 4.9 Hz, 1 H), 1.71-1.64 (m, 2H), 1.53 (ddd, J=14.4, 8.8, 1.9 Hz, 1 H), 0.94 (d, J=7.0 Hz, 3 H), 0.89(s, 9 H), 0.865 (s, 9 H), 0.862 (d, J=6.9 Hz, 3 H), 0.07 (s, 3 H), 0.04(s, 3 H), 0.03 (s, 3 H), 0.005 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d138.5, 128.3, 127.6, 127.5, 103.8, 75.5, 73.2, 72.8, 69.8, 69.1, 55.7,38.9, 38.5, 37.6, 26.0, 25.8, 18.18, 18.16, 15.1, 12.9, -3.9, -4.6,-4.7, -4.8; high resolution mass spectrum (FAB, NBA) m/z 575.3552(M+Na)⁺ ; calcd for C₃₀ H₅₆ O₅ Si₂ Na: 575.3564!.

β anomer: α!²³ _(D) +13.3° (c 1.38, CHCl₃); IR (CHCl₃) 3003 (m), 2960(s), 2935 (s), 2880 (s), 2860 (s), 1495 (w), 1470 (m), 1464 (m), 1390(m), 1360 (m), 1350 (m), 1330 (w), 1253 (s), 1155 (s), 1140 (s), 1120(s), 1090 (s), 1045 (s), 1022 (s), 1002 (s), 953 (m), 933 (m), 850 (s),830 (s), 690 (m), 658 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.32-7.22(m, 5 H), 4.74 (d, J=2.4 Hz, 1 H), 4.50 (ABq, J_(AB) =13.2 Hz, Δδ_(AB)=17.8 Hz, 2 H), 4.23-4.18 (m, 1 H), 3.74 (ddd, J=10.6, 10.6, 1.3 Hz, 1H), 3.60 (apparent t, J=2.7 Hz, 1 H), 3.48 (s, 3 H), 3.38 (dd, J=9.8,4.5 Hz, 1 H), 3.35 (dd, J=9.8, 5.7 Hz, 1 H), 1.88 (qdd, J=7.1, 2.7, 2.7Hz, 1 H), 1.66 (ddd, J=14.0, 10.1, 1.6 Hz, 1 H), 1.63-1.55 (m, 1 H),1.49 (ddd, J=14.0, 10.8, 1.8 Hz, 1 H), 0.91 (d, J=7.1 Hz, 3 H), 0.89 (s,9 H), 0.88 (s, 9 H), 0.785 (d, J=6.8 Hz, 3 H), 0.07 (s, 3 H), 0.045 (s,3 H), 0.040 (s, 3 H), 0.02 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 138.5,128.2, 127.6, 127.4, 100.6, 76.9, 75.8, 73.2, 71.7, 67.9, 56.7, 41.1,38.4, 35.0, 26.1, 25.8, 18.2, 18.1, 14.0, 9.7, -3.9, -4.5, -5.0; highresolution mass spectrum (FAB, NBA) m/z 575.3560 (M+Na)⁺ ; calcd for C₃₀H₅₆ O₅ Si₂ Na: 575.3564!.

EXAMPLE 30 Primary Alcohol 37

A solution of 36 (331.6 mg, 0.600 mmol) in EtOH/EtOAc (1:8, 9 mL) wastreated with Pd/C (10% wet, E101 NE/W, 51.2 mg) under H₂ atmosphere for3 h, then filtered and concentrated. Flash chromatography (10% ethylacetate/hexane) provided 37 (276.6 mg, β/α=2:1, 99% yield) as acolorless oil.

β anomer: α!²³ _(D) +16.9° (c 2.52, CHCl₃); IR (CHCl₃) 3680 (w), 3590(w, br), 3450 (w, br), 3000 (m), 2960 (s), 2925 (s), 2880 (m), 2855 (s),1470 (m), 1462 (m), 1388 (m), 1360 (m), 1253 (s), 1222 (m), 1200 (m),1150 (m), 1130 (m), 1110 (s), 1098 (m), 1065 (s), 1046 (s), 1023 (s),1002 (m), 980 (m), 952 (m), 894 (m), 865 (m), 850 (m), 830 (s), 663 (m),657 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 4.73 (d, J=2.5 Hz, 1 H),4.09-4.05 (m, 1 H), 3.64 (ddd, J=10.5, 10.5, 1.3 Hz, 1 H), 3.60(apparent t, J=2.5 Hz, 1 H), 3.62-3.59 (m, 1 H), 3.47 (s, 3 H),3.47-3.42 (m, 1 H), 1.95-1.85 (m, 2 H), 1.82 (ddd, J=14.3, 9.2, 1.5 Hz,1 H), 1.60 (dqd, J=10.2, 6.8, 2.5 Hz, 1 H), 1.45 (ddd, J=14.3, 10.7, 2.6Hz, 1 H), 0.895 (d, J=7.5 Hz, 3 H), 0.887 (apparent s, 18 H), 0.785 (d,J=6.8 Hz, 3 H), 0.09 (s, 3 H), 0.08 (s, 3 H), 0.04 (s, 3 H), 0.02 (s, 3H); ¹³ C NMR (125 MHZ, CDCl₃) d 100.8, 76.8, 72.2, 69.5, 67.6, 56.8,41.0, 38.2, 34.9, 25.9, 25.8, 18.1, 14.0, 9.7, -4.2, -4.6, -4.7, -5.0;high resolution mass spectrum (FAB, NBA) m/z 485.3080 (M+Na)⁺ ; calcdfor C₂₃ H₅₀ O₅ SiNa: 485.3094!.

α anomer: α!²³ _(D) +54.9° (c 1.20, CHCl₃); IR (CHCl₃) 3670 (w), 3590(w) 3440 (w, br), 3000 (m), 2960 (s), 2925 (s), 2880 (m), 2855 (s), 1463(m), 1390 (m), 1360 (m), 1255 (s), 1225 (m), 1192 (m), 1168 (m), 1143(m), 1102 (s), 1083 (s), 1045 (s), 1030 (m), 1002 (m), 963 (m), 932 (m),862 (m), 833 (s) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 4.25 (d, J=4.2 Hz, 1H), 3.89 (dddd, J=6.5, 4.6, 4.6, 4.6 Hz, 1 H), 3.80 (ddd, J=9.1, 9.1,2.3 Hz, 1 H), 3.61 (br dd, J=10.9, 3.4 Hz, 1 H), 3.51 (dd, J=6.5, 4.6Hz, 1 H), 3.52-3.48 (m, 1 H), 3.33 (s, 3 H), 2.15 (s, br, 1 H), 1.81(dqd, J=6.9, 6.9, 4.2 Hz, 1 H), 1.72-1.60 (m, 3 H), 0.94 (d, J=7.1 Hz, 3H), 0.882 (s, 9 H), 0.879 (s, 9 H), 0.845 (d, J=6.8 Hz, 3 H), 0.09 (s, 3H), 0.08 (s, 3 H), 0.02 (s, 3 H), 0.00 (s, 3 H); ¹³ C NMR (125 MHz,CDCl₃) d 104.0, 72.7, 71.3, 70.0, 67.6, 55.7, 38.7, 38.5, 37.3, 25.8,18.13, 18.08, 15.2, 13.1, -4.4, -4.6, -4.7; high resolution massspectrum (FAB, NBA) m/z 485.3081 (M+Na)⁺ ; calcd for C₂₃ H₅₀ O₅ Si₂ Na:485.3094!.

EXAMPLE 31 Alcohol 38

A solution of 37 (276.6 mg, 0.598 mmol) in Et₂ O (40 mL) was treatedwith EtSH (8.90 mL, 120 mmol) and MgBr₂.Et₂ O (1.54 g, 5.96 mmol) atroom temperature. After 60 h, the mixture was diluted with ethyl acetate(50 mL), washed with brine (2×100 mL), dried over MgSO₄, filtered andconcentrated. Flash chromatography (3% acetone/hexane) provided 38 α(34.4 mg, 12% yield) and 38 β (211.3 mg, 71% yield).

β anomer: colorless oil; α!²³ _(D) +16.6° (c 1.18, CHCl₃); IR (CHCl₃)3595 (m), 3400 (m, br), 3000 (m), 2960 (s), 2930 (s), 2855 (s), 1655(w), 1612 (s), 1588 (m), 1510 (s), 1462 (s), 1375 (m), 1360 (m), 1300(m), 1250 (s, br), 1170 (m), 1080 (s, br), 1030 (s), 1002 (m), 967 (m),835 (s) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 5.08 (d, J 2.3 Hz, 1 H),4.04-4.00 (m, 1H), 3.62 (ddd, J=10.4, 10.4, 1.0 Hz, 1 H), 3.60 (ddd,J=11.1, 11.1, 4.2 Hz, 1 H), 3.56 (apparent t, J=2.7 Hz, 1 H), 3.43 (ddd,J=11.7, 7.9, 4.1 Hz, 1 H), 2.70 (dq, J=12.7, 7.4 Hz, 1 H), 2.67 (dq,J=12.8, 7.5 Hz, 1 H), 1.95 (dd, J=7.9, 4.8 Hz, 1 H), 1.86 (qdd, J=7.1,2.7, 2.7 Hz, 1 H), 1.79 (ddd, J=14.4, 9.0, 1.4 Hz, 1 H), 1.66-1.59 (m, 1H), 1.57 (s, 3 H) 1.45 (ddd, J=14.4, 10.5, 2.7 Hz, 1 H), 1.27 (apparentt, J=7.4 Hz, 1 H), 0.99 (d, J=7.1 Hz, 3 H), 0.90 (s, 9 H), 0.89 (s, 9H), 0.79 (d, J=6.8 Hz, 3 H), 0.083 (s, 3 H), 0.075 (s, 3 H), 0.04 (s, 3H), 0.03 (s, 3 H); I3C NMR (125 MHZ, CDCl₃) d 81.0, 76.2, 75.0, 69.8,67.6, 41.9, 38.3, 34.5, 25.9, 25.8, 25.2, 18.1, 15.2, 14.4, 11.5, -4.2,-4.56, -4.63, -4.9; high resolution mass spectrum (FAB, NBA) m/z515.3037 (M+Na); calcd for C₂₄ H₅₂ O₄ SSi₂ Na: 515.3023!.

α anomer: colorless oil; α!²³ _(D) +94.5° (c 0.33, CHCl₃); IR (CHCl₃)3680 (w), 3580 (w), 3440 (w, br), 3010 (m), 2960 (s), 2930 (s), 2880(m), 2860 (s), 1513 (w), 1470 (m), 1462 (m), 1390 (m), 1380 (m), 1360(m), 1257 (s), 1225 (m), 1200 (m), 1114 (m), 1070 (s), 1047 (s), 1022(m), 1002 (m), 957 (m), 860 (m), 833 (s), 705 (s), 660 (m) cm⁻¹ ; ¹ HNMR (500 MHZ, CDCl₃) d 4.76 (d, J=3.1 Hz, 1 H), 4.04 (ddd, J=9.8, 9.8,1.8 Hz, 1 H), 3.84 (dddd, J=5.0, 5.0, 5.0, 5.0 Hz, 1 H), 3.57 (dd,J=11.0, 4.2 Hz, 1 H), 3.53 (apparent t, J=4.0 Hz, 1 H), 3.47 (dd,J=11.0, 4.7 Hz, 1 H), 2.57 (dq, J=12.8, 7.5 Hz, 1 H), 2.54 (dq, J=12.8,7.5 Hz, 1 H), 1.97-1.91 (m, 1 H), 1.75 (ddd, J=14.7, 6.1 Hz, 2.0, 1 H),1.72-1.65 (m, 1 H), 1.60 (ddd, J=14.9, 10.0, 5.1 Hz, 1 H), 1.60-1.50(br, 1 H), 1.23 (apparent t, J=7.4 Hz, 3 H), 1.06 (d, J=7.1 Hz, 3 H),0.92 (s, 9 H), 0.89 (s, 9 H), 0.85 (d, J=6.9 Hz, 3 H), 0.12 (s, 3 H),0.08 (s, 3 H), 0.05 (s, 3 H), 0.02 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d85.3, 73.8, 71.5, 69.2, 67.5, 40.6, 38.2, 36.4, 26.4, 26.1, 25.9, 18.2,18.1, 17.5, 14.7, 13.9, -4.2, -4.4, -4.8; high resolution mass spectrum(FAB, NBA) m/z 515.3045 (M+Na)⁺ ; calcd for C₂₄ H₅₂ O₄ SSi₂ Na:515.3023!.

EXAMPLE 32 Fragment (+)-C

A solution of DMSO (100 μL, 1.42 mmol) in CH₂ Cl₂ (2.0 mL) was cooled to-78° C. and oxalyl chloride (55.0 μl, 0.630 mmol) was introduceddropwise. After 15 min. a cooled (-78° C.) solution of 38 α (104.8 mg,0.213 mmol) in CH₂ Cl₂ (1.0 mL) was introduced via cannula (2×500 μLrinse). The resultant milky solution was stirred for 15 min at -78° C.and i-Pr₂ NEt (370 μl, 2.12 mmol) was added dropwise. The reactionmixture was stirred for 0.5 h, slowly warmed to room temperature (15min), and quenched with aqueous NaHSO₄ (1.0M, 4.0 mL). The organic phasewas diluted with ether (30 mL), washed with brine (3×30 mL), dried overMgSO₄, filtered and concentrated. Flash chromatography (2% ethylacetate/hexane) furnished (+)-C (88.8 mg, 86% yield) as a colorless oil:α!²³ _(D) +11.2° (c 1.42, CHCl₃); IR (CHCl₃) 2960 (s), 2935 (s), 2880(s), 2860 (s), 1735 (s), 1470 (m), 1460 (m), 1380 (m), 1360 (m), 1320(m), 1295 (w), 1265 (s), 1153 (m), 1120 (m), 1080 (m), 1060 (s), 1043(s), 1025 (s), 1003 (s), 970 (m), 950 (m), 935 (m), 903 (m), 865 (m),835 (s), 800 (m), 690 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 9.56 (d,J=0.9 Hz, 1 H), 5.07 (d, J=2.3 Hz, 1 H), 4.35 (ddd, J=7.9, 2.2, 0.6 Hz,1 H), 3.70 (ddd, J=10.3, 10.3, 1.5 Hz, 1 H), 3.57 (apparent t, J=2.7 Hz,1 H), 2.71-2.60 (m, 2 H), 1.86 (apparent qt, J=7.1, 2.7 Hz, 1 H), 1.78(ddd, J=14.1, 10.4, 7.8 Hz, 1 H), 1.72-1.66 (m, 1 H), 1.67 (ddd, J=10.3,3.9, 1.8 Hz, 1 H), 1.25 (apparent t, J=7.4 Hz, 3 H), 1.00 (d, J=7.2 Hz,3 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.78 (d, J=6.8 Hz, 3 H), 0.10 (s, 3H), 0.04 (s, 6 H), 0.03 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 202.6,81.2, 76.1, 74.9, 73.7, 41.9, 35.8, 34.4, 25.82, 25.79, 25.2, 18.2,18.1, 15.3, 14.3, 11.5, -4.2, -4.5, -4.9, -5.2; high resolution massspectrum (CI, NH₃) m/z 491.3058 (M+H)⁺ ; calcd for C₂₄ H₅₁ O₄ SSi₂ :491.3046!.

EXAMPLE 33 Fragment (-)-B

From vinyl bromide (-)-22: A solution of (-)-22 (3.78 g, 8.04 mmol) inHMPA/DMF (2:1, 6 mL) was added to a mixture of KI (4.15 g, 250 mmol),NiBr₂ (34.9 mg, 0.160 mmol), and Zn powder (23.2 mg, 0.355 mmol). Themixture was stirred at room temperature for 15 min then heated to 90° C.The green color mixture turned black-brown after 5 min and dark greenafter 1 h. After additional 1 h at 90° C., the mixture was cooled toroom temperature, diluted with ethyl acetate (200 mL), washed with brine(4×200 mL), dried over MgSO₄, filtered and concentrated. Flashchromatography (2% ethyl acetate/hexane) provided B (3.59 g, containing13% unreacted vinyl bromide) as a colorless oil.

From aldehyde (+)-18: A suspension of EtPh₃ P⁺ I⁻ (15.1 g, 36.1 mmol) inTHF (200 mL) was treated with n-BuLi (1.6M in hexane, 23.0 mL, 36.8mmol) at room temperature over 10 min. After an additional 10 min, theresultant red solution was added via cannula to a cooled (-78° C.)solution of I₂ (8.02 g, 31.6 mmol) in THF (300 mL) over 15 min. Theyellow slurry formed was stirred at -78° C. for 5 min and at -23° C. for10 min. NaHMDS (1.0M in THF, 31.0 mL, 31.0 mmol) was added over 8 minand the mixture stirred 15 min further. A solution of aldehyde (+)-18(6.96 g, 18.3 mmol) in THF (50 mL) was introduced via cannula (10 mLrinse), and the reaction mixture was stirred at -23° C. for 10 min,warmed to room temperature, stirred for 3 h, and then quenched with MeOH(10 mL). Following concentration and filtration through a silica column(50% ethyl acetate/hexane), the filtrate was washed with saturatedaqueous Na₂ S₂ O₃, brine (300 mL each), dried over MgSO₄, filtered andconcentrated. Flash chromatography (5% ethyl acetate/hexane) furnished B(6:1 Z/E, 3.94 g, 41% yield) as a colorless oil.

An analytical sample of (-)-B was obtained by reversed-phase HPLC(gradient elution, 90% CH₃ CN/H₂ O→100% CH₃ CN) α!²³ _(D) -23° (c 0.30,CHCl₃); IR (CHCl₃) 3000 (m), 2960 (s), 2930 (s), 2880 (m), 2855 (s),1610 (m), 1588 (w), 1510 (s), 1463 (m), 1453 (m), 1428 (m), 1405 (w),1390 (m), 1377 (m), 1360 (m), 1303 (m), 1250 (s), 1180 (m), 1172 (m),1080 (s, br), 1033 (s), 1002 (m), 948 (m), 935 (m), 922 (m), 833 (s) 803(m), 760 (m, br), 720 (m), 658 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d7.25 (d, J=8.6 Hz, 2 H), 6.87 (d, J=8.7 Hz, 2 H), 5.28 (apparent dd,J=8.9, 1.4 Hz, 1 H), 4.41 (ABq, J_(AB) =7.0 Hz, Δδ_(AB) =10.2 Hz, 2 H),3.80 (s, 3 H), 3.60 (apparent t, J=5.3 Hz, 1 H), 3.51 (dd, J=9.1, 5.1Hz, 1 H), 3.23 (dd, J=9.0, 8.0 Hz, 1 H), 2.54-2.47 (m, 1 H), 2.44 (d,J=1.4 Hz, 3 H), 2.00-1.92 (m, 1 H), 1.00 (d, J=6.9 Hz, 3 H), 0.95 (d, J=6.7 Hz, 3 H), 0.89 (s, 9 H), 0.02 (s, 3 H), 0.01 (s, 3 H); ¹³ C NMR(125 MHZ, CDCl₃) d 159.1, 139.6, 131.0, 129.1, 113.7, 98.9, 76.5, 72.6,72.5, 55.3, 44.5, 38.7, 33.5, 26.1, 18.4, 14.7, 14.5, -3.95, -3.99; highresolution mass spectrum (FAB, NBA) m/z 541.1626 (M+Na)⁺ ; calcd for C₂₃H₃₉ O₃ ISiNa: 541.1611!.

EXAMPLE 34 Olefin (-)-39

ZnCl₂ (1.32 g, 9.69 mmol) was dried at 160° C. under vacuum overnightand then treated with a solution of (-)-A (5.25 g, 9.59 mmol) in dry Et₂O (50 mL) via a cannula (2×25 mL rinse). The mixture was stirred at roomtemperature until most of the ZnCl₂ dissolved and cooled to -78° C.t-BuLi (1.7 M in pentane, 17.0 mL) was added over 30 min, and theresultant solution was stirred 15 min further, warmed to roomtemperature, and stirred for 1 h. The solution was added by cannula to amixture of B (3.21 g, 6.19 mmol; 6:1 Z/E) and Pd(PPh₃)₄ (364.0 mg, 0.315mmol). The mixture was covered with aluminum foil, stirred overnight,and then diluted with ethyl acetate (100 mL), washed with brine (2×100mL), dried over MgSO₄, filtered and concentrated. Flash chromatography(5% ethyl acetate/hexane) gave (-)-39 (3.32 g, 66% yield) as a whitesemisolid: α!²³ _(D) -28.6° (c 1.53, CHCl₃); IR (CHCl₃) 3010 (m), 2970(s), 2940 (s), 2865 (s), 1620 (m), 1590 (w), 1520 (s), 1465 (s), 1445(m), 1390 (m), 1380 (m), 1360 (m), 1305 (m), 1250 (s), 1175 (m), 1115(s), 1080 (s), 1040 (s), 970 (m), 940 (w), 860 (m), 835 (s) cm⁻¹ ; ¹ HNMR (500 MHZ, CDCl₃) d 7.36 (d, J=8.7 Hz, 2 H), 7.22 (d, J=8.6 Hz, 2 H),6.86 (d, J=9.0 Hz, 2 H), 6.84 (d, J=8.9 Hz, 2 H), 5.37 (s, 1 H), 5.00(d, J=10.2 Hz, 1 H), 4.36 (ABq, J_(AB) =11.6 Hz, Δδ_(AB) =17.4 Hz, 2 H),4.08 (dd, J=11.2, 4.7 Hz, 1 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 3.61 (dd,J=7.1, 1.8 Hz, 1 H), 3.51 (dd, J=9.9, 1.7 Hz, 1 H), 3.47 (apparent t,J=11.0 Hz, 1 H), 3.46 (dd, J=9.1, 5.0 Hz, 1 H), 3.38 (dd, J=6.0, 4.8 Hz,1 H), 3.19 (apparent t, J=8.8 Hz, 1 H), 2.51 (ddq, J=10.1, 6.5, 6.5 Hz,1 H), 2.32 (apparent t, J=12.2 Hz, 1 H), 2.08-2.02 (m, 1 H), 1.99-1.93(m, 2 H), 1.88 (dqd, J=7.1, 7.1, 1.8 Hz, 1 H), 1.67 (br d, J=11.1 Hz, 1H), 1.55 (d, J=0.5 Hz, 3 H), 1.01 (d, J=7.1 Hz, 3 H), 0.94 (d, J=6.9 Hz,3 H), 0.90 (s, 9 H), 0.89 (d, J=6.7 Hz, 3 H), 0.87 (s, 9 H), 0.74 (d,J=6.3 Hz, 3 H), 0.73 (d, J=6.4 Hz, 3 H), 0.03 (s, 3 H), 0.013 (s, 3 H),0.008 (s, 3 H), 0.003 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 159.8,159.0, 132.0, 131.5, 131.2, 131.1, 129.0, 127.3, 113.7, 113.5, 101.1,83.4, 78.49, 78.46, 73.3, 72.6, 72.5, 55.3, 38.8, 38.2, 37.5, 35.6,33.7, 30.8, 26.27, 26.25, 23.1, 18.42, 18.40, 17.0, 14.6, 12.6, 12.1,10.9, -3.5, -3.7, -3.8, -3.9; high resolution mass spectrum (FAB, NBA)m/z 835.5315 (M+Na)⁺ ; calcd for C₄₇ H₈₀ O₇ Si₂ Na: 835.5341!.

Anal. Calcd for C₄₇ H₈₀ O₇ Si₂ : C, 69.41; H, 9.91. Found: C, 69.52; H,10.10.

EXAMPLE 35 Alcohol (-)-40

A solution of olefin (-)-39 (2.65 g, 3.26 mmol) in CH₂ Cl₂ (32 mL) wascooled to 0° C. and treated with H₂ O (1.50 mL) and DDQ (774 mg, 3.41mmol). After 4 h, the mixture was diluted with CH₂ Cl₂ (20 mL), driedover MgSO₄, and filtered through a silica column (50% ethylacetate/hexane). Following concentration, the residue was dissolved inEtOH (50 mL) and treated with NaBH₄ (500 mg, excess) at room temperatureto reduce the contaminated p-methoxybenzyl aldehyde. After 0.5 h, themixture was quenched with saturated aqueous NH₄ Cl (50 mL) at 0° C. thenconcentrated. The residue was partitioned between CH₂ Cl₂ (200 mL) andwater (100 mL). The organic phase was washed with water (100 mL), driedover MgSO₄, filtered and concentrated. Flash chromatography (10% ethylacetate/hexane) provided (-)-40 (2.06 g, 91% yield) as a white solid. mp99°-100° C.; α!²³ _(D) -25.4° (c 1.35, CHCl₃); IR (CHCl₃) 3520 (w), 3010(m), 2960 (s), 2940 (s), 2880 (m), 2860 (m), 1620 (m), 1593 (w), 1520(m), 1565 (m), 1390 (m), 1360 (m), 1255 (s), 1175 (m), 1165 (m), 1117(m), 1075 (s), 1037 (s), 1025 (s), 1005 (m), 982 (m), 965 (m), 930 (w),835 (s), 800 (m), 705 (w), 675 (w), 660 (w) cm⁻¹ ; ¹ H NMR (500 MHZ,CDCl₃) d 7.36 (d, J=8.7 Hz, 2 H), 6.86 (d, J=8.8 Hz, 2 H), 5.37 (s, 1H), 5.01 (d, J=10.1 Hz, 1 H), 4.09 (dd, J=11.2, 4.7 Hz, 1 H), 3.79 (s, 3H), 3.65 (dd, J=10.4, 4.7 Hz, 1 H), 3.63 (dd, J=7.0, 1.8 Hz, 1 H),3.54-3.50 (m, 1 H), 3.51 (dd, J=10.0, 2.0 Hz, 1 H), 3.47 (apparent t,J=11.2 Hz, 1 H), 3.41 (dd, J=6.6, 4.0 Hz, 1 H), 2.59 (ddq, J=13.2, 6.7,6.7 Hz, 1 H), 2.33 (apparent t, J=12.2 Hz, 1 H), 2.24 (apparent t, J=5.5Hz, 1 H), 2.09-1.95 (m, 2 H), 1.89 (dqd, J=7.0, 7.0, 1.7 Hz, 1 H),1.84-1.77 (m, 1 H), 1.72 (br d J=11.0 Hz, 1 H), 1.58 (d, J=0.8 Hz, 3 H),1.01 (d, J=7.1 Hz, 3 H), 0.98 (d, J=7.1 Hz, 3 H), 0.94 (d, J=6.7 Hz, 3H), 0.910 (s, 9 H), 0.905 (s, 9 H), 0.75 (d, J=7.1 Hz, 3 H), 0.74 (d,J=7.1 Hz, 3 H), 0.09 (s, 3 H), 0.07 (s, 3 H), 0.05 (s, 3 H), 0.01 (s, 3H); ¹³ C NMR (125 MHZ, CDCl₃) d 159.8, 133.0, 131.5, 130.5, 127.3,113.4, 101.0, 83.3, 81.6, 78.4, 73.3, 65.4, 55.3, 38.5, 38.2, 37.6,37.0, 33.7, 30.8, 26.17, 26.16, 23.2, 18.4, 18.3, 17.4, 15.7, 12.6,12.1, 10.9, -3.57, -3.61, -3.66, -3.9; high resolution mass spectrum(CI, NH,) m/z 693.4918 (M+H)⁺ ; calcd for C₃₉ H₇₃ O₆ Si₂ : 693.4945!.

Anal. Calcd for C₃₉ H₇₂ O₆ Si₂ : C, 67.58; H, 10.47. Found: C, 67.30; H,10.54.

EXAMPLE 36 Phosphonium Salt (-)-49

A solution of alcohol (-)-40 (402.8 mg, 0.577 mmol) in PhH/Et₂ O (1:2,45 mL) was treated with PPh₃ (532 mg, 2.03 mmol) and imidazole (158 mg,2.32 mmol). After the imidazole dissolved, I₂ (437 mg, 1.72 mmol) wasadded under vigorous stirring. The mixture was stirred 2 h and thentreated with NEt₃ (2 mL). The resultant yellow suspension was dilutedwith CH₂ Cl₂ (50 mL) and washed with saturated aqueous Na₂ S₂ O₃ (100mL), saturated aqueous NaHCO₃ (100 mL), and brine (2×100 mL). Theorganic phase was dried over MgSO₄, filtered and concentrated.Filtration through a short silica column (NEt₃ /ethyl acetate/hexane,2:10:90) removed triphenylphosphine oxide, affording the impure iodide42. Preparative TLC (500 mm silica gel plate, 4% acetone/hexane)furnished an analytical sample as an unstable white solid: ¹ H NMR (500MHZ, CDCl₃) d 7.35 (d, J=8.8 Hz, 2 H), 6.85 (d, J=8.7 Hz, 2 H), 5.37 (s,1 H), 5.02 (d, J=10.2 Hz, 1 H), 4.08 (dd, J=11.2, 4.7 Hz, 1 H), 3.78 (s,3 H), 3.62 (dd, J=7.0, 1.8 Hz, 1 H), 3.51 (dd, J=9.9, 1.7 Hz, 1 H), 3.47(apparent t, J=11.1 Hz, 1 H), 3.37 (dd, J=6.3, 4.3 Hz, 1 H), 3.32 (dd,J=9.6, 4.5 Hz, 1 H), 2.99 (dd, J=9.5, 8.6 Hz, 1 H), 2.50 (ddq, J=10.2,6.5, 6.5 Hz, 1 H), 2.31 (apparent t, J 12.2 Hz, 1 H), 2.08-1.95 (m, 2H), 1.88 (dqd, J=7.1, 7.1, 1.7 Hz, 1 H), 1.85-1.78 (m, 1 H), 1.74 (br d,J=11.7 Hz, 1 H), 1.57 (apparent s, 3 H), 1.01 (apparent d, J=7.0 Hz, 6H), 0.91-0.89 (m, 3 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.74 (d, J=6.8 Hz,3 H), 0.73 (d, J=6.7 Hz, 3 H), 0.06 (s, 3 H), 0.05 (s, 3 H), 0.01 (s, 3H), -0.02 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃ /1% pyridine-d₅, 20 mgsample) d 159.8, 132.9, 131.5, 130.4, 127.3, 113.5, 101.1, 83.3, 79.6,78.5, 73.3, 55.3, 41.4, 38.3, 37.6, 36.0, 33.7, 30.8, 26.20, 26.17,23.2, 18.4, 17.7, 17.3, 13.5, 12.6, 12.2, 10.9, -3.5, -3.6, -4.0; highresolution mass spectrum (FAB, NBA) m/z 803.3935 (M+H)⁺ ; calcd for C₃₉H₇₂ O₅ ISi₂ : 803.3963!.

The very sensitive impure iodide (obtained by filtration through silica)was quickly mixed with i-Pr₂ NEt (300 μL, 1.72 mmol) and PPh₃ (2.47 g,9.42 mmol). The mixture was heated at 80° C. for 24 h, then cooled toroom temperature and extracted with hexane (2×30 mL). The residue waspurified by flash chromatography (2% MeOH/CHCl₃) furnishing (-)-49(224.9 mg, 37i yield from (-)-39) as a pale yellow foam. The hexaneextract was concentrated and purified by flash chromatography (2% ethylacetate/hexane) affording a mixture of cyclization products (200 mg).Further purification by normal phase HPLC (1.5% ethyl acetate/hexane)provided (-)-50 as the major cyclization product.

Wittig reagent (-)-49: α!²³ _(D) -25.3° (c 1.48, CHCl₃); IR (CHCl₃) 2960(s), 2930 (s), 2860 (m), 1615 (m), 1590 (w) 1515 (m), 1485 (w), 1460(m), 1440 (m), 1385 (m), 1360 (m), 1300 (m), 1250 (s), 1215 (m, br),1180 (m), 1110 (s), 1080 (m), 1025 (m), 1005 (m), 965 (m), 945 (w), 860(m), 830 (s), 732 (m), 725 (m), 710 (m), 680 (m), 653 (m) cm⁻¹ ; ¹ H NMR(500 MHZ, CDCl₃ ; concentration dependent) d 7.82-7.76 (m, 15 H), 7.35(d, J=8.8 Hz, 2 H), 6.84 (d, J=8.8 Hz, 2 H), 5.35 (s, 1 H), 5.30 (d,J=10.5 Hz, 1 H), 4.07 (dd, J=11.2, 4.7 Hz, 1 H), 3.77 (s, 3 H),3.73-3.67 (m, 2 H), 3.56 (dd, J=7.0, 1.8 Hz, 1 H), 3.48 (dd, J=9.8, 1.7Hz, 1 H), 3.46 (apparent t, J=11.1 Hz, 1 H), 3.31 (ddd, J=15.6, 11.2,11.2 Hz, 1 H), 2.49 (ddq, J=10.5, 6.4, 6.4 Hz, 1 H), 2.25 (apparent t,J=12.1 Hz, 1 H), 2.10-1.92 (m, 3 H), 1.85 (dqd, J=7.1, 7.1, 1.8 Hz, 1H), 1.57-1.52 (m, 1 H), 1.56 (s, 3 H), 0.98 (d, J=7.1 Hz, 3 H), 0.89 (d,J=6.6 Hz, 3 H), 0.852 (s, 9 H), 0.849 (s, 9 H), 0.72-0.71 (m, 3 H), 0.71(d, J=6.6 Hz, 3 H), 0.69 (d, J=6.9 Hz, 3 H), 0.10 (s, 3 H), -0.02 (s, 3H), -0.03 (s, 3 H), -0.07 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 159.8,135.2 (J_(CP) =2.6 Hz), 133.5 (J_(CP) =10.0 Hz), 132.9, 131.4, 130.6(J_(CP) =12.6 Hz), 130.3, 127.3, 118.4 (J_(CP) =85.5 Hz), 113.4, 101.0,83.2, 80.1 (J_(CP) =14.0 Hz), 78.3, 73.2, 55.3, 38.1, 37.4, 36.0, 33.7(J_(CP) =4.4 Hz), 33.6, 30.7, 26.1, 25.5 (J_(CP) =49.7 Hz), 22.9, 18.33,18.29, 17.2, 17.1, 12.5, 12.1, 10.9, -3.2, -3.6, -3.7, -4.0; highresolution mass spectrum (FAB, NBA) m/z 937.5708 (M-I)⁺ ; calcd for C₅₇H₈₆ O₅ PSi₂ : 937.5751!.

Olefin (-)50: white solid; mp 80°-82° C.; α!²³ _(D) -18° (c 0.48,CHCl₃); IR (CHCl₃) 2955 (s), 2920 (s), 2880 (m), 2850 (s), 1640 (w),1613 (m), 1588 (w), 1517 (m), 1460 (m), 1387 (m), 1360 (m), 1300 (m),1250 (s), 1178 (m), 1170 (m), 1160 (m), 1115 (m), 1080 (m), 1023 (s),1000 (m), 980 (m), 960 (m), 930 (w), 887 (m), 855 (m), 830 (m), 715 (m)cm⁻¹ ; ¹ H NMR (500 MHZ, C₆ D₆) d 7.62 (d, J=8.7 Hz, 2 H), 6.83 (d,J=8.7 Hz, 2 H), 5.46 (s, 1 H), 5.00 (s, 1 H), 4.95 (s, 1 H), 3.93 (dd,J=11.1, 4.7 Hz, 1 H), 3.89 (dd, J=7.2, 1.5 Hz, 1 H), 3.55 (dd, J=9.9,1.9 Hz, 1 H), 3.51 (apparent t, J=5.9 Hz, 1 H), 3.27 (s, 3 H), 3.22(apparent t, J=11.0 Hz, 1 H), 2.32 (dd, J=13.6, 3.5 Hz, 1 H), 2.27-2.20(m, 1 H), 2.16 (dd, J=13.7, 9.5 Hz, 1 H), 2.07-1.92 (m, 4 H), 1.87-1.80(m, 1 H), 1.50-1.42 (m, 1 H), 1.18 (d, J=7.1 Hz, 3 H), 1.10 (d, J=6.6Hz, 3 H), 1.06 (d, J=6.6 Hz, 3 H), 1.04 (s, 9 H), 1.02 (d, J=7.0 Hz, 3H), 1.00 (s, 9 H), 0.41 (d, J=6.7 Hz, 3 H), 0.13 (s, 3 H), 0.09 (s, 3H), 0.08 (s, 3 H), 0.06 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 159.8 (q),150.7 (q), 131.5 (q), 127.3, 113.4, 108.3 (CH₂), 101.0, 83.2, 81.9,78.1, 73.3 (CH₂), 55.2, 49.9, 44.9, 41.4 (CH₂), 39.0 (CH₂), 38.3, 36.6,33.4, 30.8, 26.3, 25.9, 18.5 (q), 18.2 (q), 17.8, 15.5, 12.9, 12.1,11.0, -3.4, -3.7, -4.6, -4.7; high resolution mass spectrum (FAB, NBA)m/z 697.4642 (M+Na)⁺ ; calcd for C₃₉ H₇₀ O₅ Si₂ Na: 697.4659!.

EXAMPLE 37 Model Olefin (+)-43

NaHMDS (0.6M in PhMe, 9.46 mL, 5.68 mmol) was added over 10 min to asuspension of (CH₃)₂ CHP⁺ Ph₃ I⁻ (2.52 g, 5.83 mmol) in PhMe (20 mL) atroom temperature. After 15 min, the mixture was cooled to -78° C., andaldehyde (+)-18 (1.46 g, 3.84 mmol) in PhMe (15 mL) was introduced via acannula (15mL rinse). After 20 min at -78° C. and 30 min at roomtemperature, the reaction was quenched with MeOH (1.0 mL). The solutionwas separated, and the oil residue was extracted with hexane (3×30 mL).The combined organic solutions were then concentrated and, and flashchromatography (20 ethyl acetate/hexane) provided (+)-43 (1.44 g, 92%yield) as a colorless oil: α!²³ _(D) +8.07° (c 2.57, CHCl₃); IR (CHCl₃)2960 (s), 2925 (s), 2880 (s), 2855 (s), 1610 (m), 1585 (m), 1510 (s),1460 (s), 1375 (m), 1360 (m), 1300 (m), 1245 (s), 1172 (m), 1085 (s,br), 1035 (s), 1003 (m), 970 (m), 950 (m), 935 (m), 862 (s), 835 (s)cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.23 (d, J=9.0 Hz, 2 H), 6.85 (d,J=8.6 Hz, 2 H), 4.92 (d-quintet, J=9.7, 1.4 Hz, 1 H), 4.37 (apparent s,2 H), 3.78 (s, 3 H), 3.49 (dd, J=9.2, 4.9 Hz, 1 H), 3.39 (dd, J=6.3, 4.5Hz, 1 H), 3.19 (dd, J=9.0, 8.4 Hz, 1 H), 2.49 (ddq, J=9.6, 6.7, 6.7 Hz,1 H), 2.00-1.92 (m, 1 H), 1.63 (d, J=1.2 Hz, 3 H), 1.55 (d, J=1.3 Hz, 3H), 0.945 (d, J=7.0 Hz, 3 H), 0.874 (d, J=6.7 Hz, 3 H), 0.873 (s, 9 H),0.01 (apparent s, 6 H); ¹³ C NMR (125 MHZ, CDCl₃) 159.0, 131.1, 129.7,129.4, 129.1, 113.7, 78.6, 72.6, 55.3, 38.5, 36.0, 26.2, 25.8, 18.4,17.9, 17.0, 14.8, -3.88, -3.95; high resolution mass spectrum (CI, NH₃)m/z 407.2984 (M+H)⁺ ; calcd for C₂₄ H₄₃ O₃ Si: 407.2981!.

EXAMPLE 38 Alcohol (+)-44

A mixture of olefin (+)-43 (387.6 mg, 0.954 mmol) in CH₂ Cl₂ (10 mL) wastreated with H₂ O (500 μL) and DDQ (320 mg, 1.41 mmol). After 30 min atroom temperature, the mixture was filtered through a short silica plug(50% ethyl acetate/hexane) and concentrated. Flash chromatography (3%ethyl acetate/hexane) provided (+)-43 (273.1 mg, 99% yield) as acolorless oil: α!²³ _(D) +17.5° (c 2.80, CHCl₃); IR (CHCl₃) 3620 (w),3500 (m, br), 2955 (s), 2925 (s), 2880 (s), 2860 (s), 1460 (s), 1405(m), 1375 (m), 1360 (m), 1337 (m), 1252 (s), 1070 (s), 1050 (s), 1015(s), 1002 (s), 978 (m), 933 (m), 832 (s) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃)d 4.92 (apparent d quintet, J=9.7, 1.4 Hz, 1 H), 3.66 (ddd, J=11.0, 4.4,4.4 Hz, 1 H), 3.52 (ddd, J=11.0, 5.5, 5.5 Hz, 1 H), 3.42 (dd, J=6.8, 4.0Hz, 1 H), 2.57 (ddq, J=9.6, 6.8, 6.8 Hz, 1 H), 2.45 (apparent t, J=5.2Hz, 1 H), 1.85-1.78 (m, 1 H), 1.65 (d, J=1.3 Hz, 3 H), 1.59 (d, J=1.3Hz, 3 H), 0.98 (d, J=7.1 Hz, 3 H), 0.92 (d, J=6.8 Hz, 3 H), 0.90 (s, 9H), 0.08 (s, 3 H), 0.05 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 130.7,128.5, 81.7, 65.5, 38.1, 37.4, 26.2, 25.8, 18.3, 17.9, 17.4, 15.9, -3.7,-3.9; high resolution mass spectrum (CI, NH₃) m/z 287.2418 (M+H)⁺ ;calcd for C₁₆ H₃₅ O₂ Si: 287.2406!.

EXAMPLE 39 Wittig reagent (+)-46

Iodine (1.08 g, 4.24 mmol) was added to a solution of alcohol (+)-44(810 mg, 2.83 mmol), PPh₃ (1.11 g, 4.24 mmol) and imidazole (289 mg,4.24 mmol) in benzene/ether (1:2, 21 mL) under vigorous stirring at roomtemperature. After 40 min, the mixture was diluted with ether (100 mL),washed with saturated Na₂ S₂ O₃ (50 mL), brine (100 mL), dried overMgSO₄, filtered and concentrated. Flash chromatography (hexane) provideda mixture of 45/47/48 (1.06 g, 97% yield, 18:1:1) as a colorless oil;This material was then treated with I-Pr₂ NEt (928 μL, 5.33 mmol) andPPh₃ (7.01 g, 26.7 mmol) then heated at 80° C. for 13 h. The mixture wasextracted with hexane (3×100 mL). The residue was purified by flashchromatography (2% MeOH/CHCl₃) providing Wittig reagent (+)-48 (207.1mg, 38% yield from (+)-46) as a pale yellow foam. The hexane extract wasconcentrated and purified by flash chromatography (hexane) affording amixture of two cyclization products (380 mg) and further purification bypreparative TLC (hexane) afforded (-)-49 and (-)-50.

Wittig reagent (+)-46: α!²³ _(D) +4.8° (c 1.23, CHCl₃); IR (CHCl₃) 2940(s), 2860 (m), 1588 (w), 1482 (w), 1468 (m) 1460 (m), 1440 (s), 1380(m), 1360 (w), 1310 (w), 1253 (m) 1230 (m), 1210 (m), 1110 (s), 1080(m), 1050 (m), 1018 (m) 1000 (m), 995 (m), 860 (m), 832 (s), 800 (m),708 (m), 680 (m), 652 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃ ; concentrationdependent) d 7.81-7.67 (m, 15 H), 4.92 (d, J=9.7 Hz, 1 H), 3.50(apparent t, J=5.3 Hz, 1 H), 3.38 (ddd, J=14.9, 14.9, 1.5 Hz, 1 H), 3.25(ddd, J=15.6, 11.1, 11.1 Hz, 1 H), 2.42 (ddq, J=9.7, 6.6, 6.6 Hz, 1 H),2.10-2.00 (m, 1 H), 1.53 (s, 3 H), 1.43 (s, 3 H), 0.83 (s, 9 H), 0.81(d, J=6.7 Hz, 3 H), 0.75 (d, J=6.8 Hz, 3 H), 0.03 (s, 3 H), -0.02 (s, 3H); ¹³ C NMR (125 MHZ, CDCl₃) d, 135.3 (J_(cp) =2.8 Hz), 133.3 (J_(cp)=9.9 Hz), 131.0, 130.6 (J_(cp) =12.4 Hz), 128.0, 118.2 (J_(cp) =85.6Hz), 80.4 (J_(cp) =13.3 Hz), 36.0, 33.0 (J_(cp) =4.0 Hz), 26.1, 25.6,25.1 (J_(cp) =50.8 Hz), 18.3, 18.1, 17.9, 16.4, -3.3, -4.0; highresolution mass spectrum (FAB, NBA) m/z 531.3221 (M-I)⁺ ; calcd for C₃₄H₄₈ OPSi: 531.3213!.

Olefin (-)-47: Colorless oil; α!²³ _(D) -14° (c 0.36, CHCl₃); IR (CHCl₃)2960 (s), 2930 (s), 2860 (s), 1470 (m), 1460, 1370 (m), 1360 (m), 1250(m), 1206 (w), 1165 (m), 1140 (m) 1070 (s), 1020 (s), 1000 (m), 932 (w),908 (w), 897 (w), 853 (m), 830 (s) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d3.63 (d, br, J=3.6 Hz, 1 H), 2.50 (apparent q, J=7.3 Hz, 1 H), 2.28(ddd, J=15.5, 7.7, 0.8 Hz, 1 H), 2.13-2.03 (m, 1 H), 1.99-1.91 (m, 1 H),1.60 (apparent br s, 3 H), 1.57 (apparent d, J=0.8 Hz, 1 H), 0.94 (d,J=6.7 Hz, 3 H), 0.91 (d, J=7.4 Hz, 3 H), 0.85 (s, 9 H), 0.01 (apparents, 6 H); ¹³ C NMR (125 MHZ, CDCl₃) d 138.9 (q), 122.0 (q), 82.9, 46.1,36.4, 35.8 (CH₂), 25.9, 21.2, 20.4, 18.3 (q), 18.0, 14.3, -4.6, -4.8;high resolution mass spectrum (CI, NH₃) m/z 269.2310 (M+H)⁺ ; calcd forC₁₆ H₃₃ OSi: 269.2300!.

Olefin (-)-48: Colorless oil; α!²³ _(D) -3.8° (c 0.24, CHCl₃); IR(CHCl₃) 2953 (s), 2925 (s), 2880 (m), 2855 (m), 1638 (w), 1470 (m), 1460(m), 1385 (w), 1373 (m), 1360 (w), 1250 (m), 1135 (m), 1117 (m), 1100(m), 1075 (m), 1028 (m), 1000 (m), 932 (w), 865 (m), 830 (s) cm⁻¹ ; ¹ HNMR (500 MHZ, C₆ D₆) d 4.84-4.83 (m, 1 H), 4.79-4.77 (m, 1 H), 3.46(apparent t, J=5.3 Hz, 1 H), 1.94-1.88 (m, 1 H), 1.87-1.78 (m, 2 H),1.73 (ddd, J=12.4, 7.3, 7.3 Hz, 1 H), 1.66 (apparent dd, J=1.3, 0.8 Hz,3 H), 1.45 (ddd, J=12.2, 10.3, 8.7 Hz, 1 H), 1.00 (d, J=6.9 Hz, 3 H),0.99 (s, 9 H), 0.96 (d, J=6.7 Hz, 3 H), 0.06 (s, 3 H), 0.05 (s, 3 H); ¹³C NMR (125 MHZ, C₆ D₆) d 147.4 (q), 110.3 (CH₂), 82.3, 53.1, 45.4, 37.5(CH₂), 37.3, 26.1, 19.3, 18.4 (q), 18.0, 15.6, -4.4, -4.5; highresolution mass spectrum (CI, NH,) m/z 269.2315 (M+H)⁺ ; calcd for C₁₆H₃₃ OSi: 269.2300!.

EXAMPLE 40 Alcohol (+)-51

A solution of olefin (+)-44 (70.9 mg, 0.28 mmol) in EtOH/EtOAc (1:8, 4.5mL) was treated with Pd/C (10% wet, E101 NE/W, 15.2 mg) under H₂atmosphere for 18 h. The mixture was then filtered through a shortsilica pipet and concentrated. Flash chromatography (5% ethylacetate/hexane) provided (+)-51 (70.8 mg, 100% yield) as a colorlessoil. α!²³ _(D) +28° (c 0.15, CHCl₃); IR (CHCl₃) 3680 (w), 3620 (w), 3500(w, br), 3010 (m) 2960 (s), 2935 (s), 2900 (m), 2885 (m), 2860 (m), 1522(w) 1510 (w), 1470 (m), 1426 (m), 1420 (m), 1412 (m), 1387 (m) 1370 (m),1255 (m), 1205 (m), 1070 (m), 1030 (m), 1013 (m), 1002 (m), 980 (m), 925(m), 833 (s), 720 (m), 665 (m), 658 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃)d 3.60-3.56 (m, 2 H), 3.46 (dd, J=5.5, 3.8 Hz, 1 H), 2.46 (br s, 1 H),1.89-1.81 (m, 1 H), 1.74-1.66 (m, 1 H), 1.64-1.56 (m, 1 H), 1.21 (ddd,J=13.3, 8.9, 4.6 Hz, 1 H), 1.09 (ddd, J=13.7, 9.6, 5.3 Hz, 1 H), 0.94(d, J=7.0 Hz, 3 H), 0.90 (s, 9 H), 0.88 (d, J=6.6 Hz, 3 H), 0.86 (d,J=6.9 Hz, 3 H), 0.83 (d, J=6.6 Hz, 3 H), 0.095 (s, 3 H), 0.07 (s, 3 H);¹³ C NMR (125 MHZ, CDCl₃) d 81.3, 66.3, 42.5, 37.8, 35.7, 26.1, 25.4,23.8, 21.8, 16.4, 15.1, -3.9, -4.1; high resolution mass spectrum (CI,NH₃) m/z 289.2565 (M+H)⁺ ; calcd for C₁₆ H₃₇ O₂ Si: 289.2562!.

EXAMPLE 41 Iodide (+)-52

A solution of alcohol (+)-51 (150 mg, 0.520 mmol), PPh₃ (205 mg, 0.780mmol) and imidazole (53 mg, 0.780 mmol) in benzene/ether (1:2; 6.0 mL)was treated with iodine (198 mg, 0.780 mmol) under vigorous stirring atroom temperature. After 40 min, the mixture was diluted with ether (100mL), washed with saturated Na₂ S₂ O₃ (50 mL), brine (100 mL), dried overMgSO₄, filtered and concentrated. Flash chromatography (hexane) provided(+)-51 (195 mg, 94% yield) as a colorless oil: α!²³ _(D) +24.2° (c 2.21,CHCl₃); IR (CHCl₃) 2960 (s), 2935 (s), 2900 (m), 2860 (s), 1470 (m),1463 (m), 1425 (w), 1405 (w), 1382 (m), 1368 (m), 1360 (m), 1290 (w),1255 (s), 1190 (m), 1170 (m), 1082 (s), 1065 (m), 1028 (m), 1003 (m),970 (w), 932 (w), 832 (s) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 3.41 (dd,J=9.6, 3.7 Hz, 1 H), 3.38 (dd, J=6.3, 2.6 Hz, 1 H), 3.10 (dd, J=9.6, 7.5Hz, 1 H), 1.72-1.56 (m, 3 H), 1.17 (ddd, J=13.4, 8.3, 5.4 Hz, 1 H), 1.09(ddd, J=13.3, 5.9, 2.1 Hz, 1 H), 0.99 (d, J=6.8 Hz, 3 H), 0.89 (s, 9 H),0.88 (d, J=6.6 Hz, 3 H), 0.84 (d, J=6.6 Hz, 3 H), 0.81 (d, J=6.8 Hz, 3H), 0.09 (s, 3 H), 0.06 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 79.1,43.7, 39.8, 33.8, 26.2, 25.3, 23.5, 22.0, 18.7, 18.5, 15.9, 14.4, -3.65,-3.71; high resolution mass spectrum (CI, NH₃) m/z 399.1572 (M+H)⁺ ;calcd for C₁₆ H₃₆ OISi: 399.1580!.

EXAMPLE 42 Wittig Reagent (+)-53

A mixture of Iodide (+)-52 (195 mg, 0.489 mmol) and benzene (100 mL) wastreated with i-Pr₂ NEt (85 μL, 0.488 mmol) and PPh₃ (1.28 g, 4.88 mmol),then heated at 70° C. for 24 h. The mixture was extracted with hexane(3×20 mL). The residue was purified by flash chromatography (3%MeOH/CHCl₃) furnishing (+)-53 (303 mg, 94% yield) as a white foam; α!²³_(D) +3.3° (c 2.14, CHCl₃); IR (CHCl₃) 2950 (s), 2930 (s), 2855 (m),1588 (w), 1482 (w), 1463 (m), 1438 (s), 1385 (m), 1365 (w), 1253 (m),1225 (m), 1207 (m), 1110 (s), 1080 (m), 1032 (m), 1000 (m), 832 (s), 804(m), 708 (m), 680 (m), 653 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d7.83-7.67 (m, 15 H), 3.70 (ddd, J=15.6, 11.0, 11.0 Hz, 1 H), 3.52 (dd,J=7.6, 1.7 Hz, 1 H), 3.45 (apparent t, J=15.4 Hz, 1 H), 2.08-1.97 (m, 1H), 1.70-1.62 (m, 1 H), 1.51 (9 lines, J=6.5 Hz, 1 H), 1.09-0.97 (m, 2H), 0.850 (s, 9 H), 0.79 (d, J=6.7 Hz, 3 H), 0.77 (d, J=7.9 Hz, 3 H),0.74 (d, J=6.5 Hz, 3 H), 0.68 (d, J=6.8 Hz, 3 H), 0.12 (s, 3 H), 0.11(s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 135.2 (J_(cp) =2.7 Hz), 133.6(J_(cp) =9.9 Hz), 130.6 (J_(cp) =12.4 Hz), 118.5 (J_(cp) =85.5 Hz), 80.1(J_(cp) =12.9 Hz), 43.5, 33.6, 32.6 (J_(cp) =3.7 Hz), 26.2, 25.3 (J_(cp)=51.1 Hz), 25.0, 23.4, 21.7, 18.6, 18.5, 13.7, -2.7, -3.8; highresolution mass spectrum (FAB,NBA) m/z 533.3369 (M-I)⁺ ; calcd for C₃₄H₅₀ OPSi: 533.3357!.

EXAMPLE 43 Olefin (-)-54

Phosphonium salt (-)-49 was dried azeotropically with anhydrous benzeneand heated at 50° C. under vacuum for 3 h before use. A solution of(-)-49 (97.7 mg, 0.0917 mmol) in THF (700 μL) was cooled to -78° C. andtreated with NaHMDS (1.0M in THF, 85.5 μL, 0.0855 mmol). The mixture wasstirred for 20 min at 0° C., recooled to -78° C. and aldehyde C (28.0mg, 0.0570 mmol) in THF (300 μL) was added. After 10 min at -78° C. and2 h at room temperature, the mixture was quenched with saturated aqueousNH₄ Cl (1.0 mL) and extracted with ether (30 mL). The ether solution waswashed with water, brine (30 mL each), dried over MgSO₄, filtered andconcentrated. Flash chromatography (2% ethyl acetate/hexane) provided(-)-56 (50.0 mg, 76% yield) as a colorless oil: α!²³ _(D) -44.9° (c2.09, CHCl₃); IR (CHCl₃) 2960 (s), 2930 (s), 2855 (s), 1615 (m), 1587(w), 1517 (m), 1463 (s), 1380 (m), 1360 (m), 1320 (m), 1300 (m), 1250(s), 1170 (m), 1160 (m), 1120-1000 (s, br), 990 (m), 965 (m), 935 (m),900 (m), 835 (s), 807 (m), 670 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d7.35 (d, J=8.7 Hz, 2 H), 6.85 (d, J=8.8 Hz, 2 H), 5.37 (s, 1 H), 5.27(dd, J=11.2, 7.8 Hz, 1 H), 5.19 (apparent t, J=10.9 Hz, 1 H), 5.08 (d,J=10.1 Hz, 1 H), 5.06 (d, J=2.2 Hz, 1 H), 4.68 (apparent t, J=9.1 Hz, 1H), 4.08 (dd, J=11.2, 4.7 Hz, 1 H), 3.78 (s, 3 H), 3.68 (apparent t,J=10.1 Hz, 1 H), 3.61 (dd, J=7.1, 1.7 Hz, 1 H), 3.53 (apparent t, J=2.6Hz, 1 H), 3.50 (dd, J=9.9, 1.6 Hz, 1 H), 3.46 (apparent t, J=11.1 Hz, 1H), 3.25 (apparent t, J=5.3 Hz, 1 H), 2.71-2.58 (m, 1 H), 2.68 (dq,J=12.8, 7.4 Hz, 1 H), 2.62 (dq, J=12.8, 7.4 Hz, 1 H), 2.50 (m, 1 H),2.30 (apparent t, J=12.2 Hz, 1 H), 2.08-2.01 (m, 1 H), 1.98-1.90 (m, 1H), 1.88 (dqd, J=7.1, 7.1, 1.7 Hz, 1 H), 1.82 (apparent qt, J=7.1, 2.6Hz, 1 H), 1.65 (br d, J=12.4 Hz, 1 H), 1.62-1.57 (m, 2 H), 1.56 (d,J=0.4 Hz, 3 H), 1.38 (ddd, J=13.6, 10.7, 1.5 Hz, 1 H), 1.29-1.22(apparent t, J=7.4 Hz, 3 H), 1.00 (d, J =7.1 Hz, 3 H), 0.94 (d, J=7.3Hz, 3 H), 0.930 (d, J=6.9 Hz, 3 H), 0.925 (d, J=7.1 Hz, 3 H), 0.90 (s,18 H), 0.89 (s, 9 H), 0.86 (s, 9 H), 0.74 (apparent d, J=6.6 Hz, 6 H),0.73 (d, J=6.1 Hz, 3 H), 0.05 (s, 3 H), 0.04 (s, 3 H), 0.03 (s, 3 H),0.019 (s, 3 H), 0.017 (s, 3 H), 0.013 (s, 3 H), 0.009 (s, 3 H), 0.00 (s,3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 159.8, 134.4, 131.9, 131.8, 131.5,131.4, 127.3, 113.4, 101.0, 83.4, 80.9, 80.4, 78.5, 76.7, 76.5, 74.2,73.3, 65.5, 55.2, 42.5, 41.9, 38.2, 37.5, 37.1, 35.4, 34.4, 33.8, 26.3,26.2, 26.0, 25.9, 25.1, 23.2, 18.5, 18.4, 18.12, 18.08, 17.0, 16.6,15.6, 14.4, 12.7, 12.1, 11.6, 10.9, -2.7, -3.5, -3.66, -3.69, -4.2,-4.5, -4.9, -5.0; high resolution mass spectrum (FAB, NBA) m/z 1171.7799(M+Na)⁺ ; calcd for C₆₃ H₁₂₀ O₈ SSi₄ Na: 1171.7781!.

EXAMPLE 44 Hydroxy Diene (-)-55

A solution of the olefin (-)-54 (49.8 mg, 0.0434 mmol) in CH₂ Cl₂ (4.4mL) was cooled to -78° C. and DIBAL (1.0M in toluene, 430 μL, 0.430mmol) was added over 5 min. After 10 min at -78° C. and 30 min at 0° C.,the reaction was quenched with saturated aqueous Rochelle's salt (500μL). The mixture was diluted with ether (60 mL), washed with saturatedaqueous Rochelle salt, brine (30 mL each), dried over MgSO₄, filteredand concentrated. Flash chromatography (5% ethyl acetate/hexane)furnished (-)-57 (38.0 mg, 88% yield) as a colorless oil: α!²³ _(D) -32°(c 1.90, CHCl₃); IR (CHCl₃) 3500 (w, br), 2960 (s), 2935 (s), 2900 (m),2885 (m), 2860 (s), 1610 (m), 1585 (w), 1510 (m), 1470 (m), 1460 (m),1400 (m), 1375 (m), 1360 (m), 1300 (m), 1250 (s), 1170 (m), 1095 (m),1080 (m), 1047 (s), 1000 (m), 960 (m), 950 (m), 933 (m), 835 (s), 805(m), 665 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.24 (d, J=8.6 Hz, 2 H),6.85 (d, J=8.6 Hz, 2 H), 5.27 (dd, J=11.4, 7.8 Hz, 1 H), 5.20 (apparentt, J=10.3 Hz, 1 H), 5.10 (d, J =10.0 Hz, 1 H), 5.05 (d, J=2.2 Hz, 1 H),4.68 (apparent t, J=9.2 Hz, 1 H), 4.49 (ABq, JAB=10.4 Hz, Δδ_(AB) =23.4Hz, 2 H), 3.78 (s, 3 H), 3.73 (ddd, J=10.7, 4.0, 4.0 Hz, 1 H), 3.68(apparent t, J=10.4 Hz, 1 H), 3.57 (ddd, J=10.6, 5.1, 5.1 Hz, 1 H), 3.53(dd, J=5.4, 3.4 Hz, 1 H), 3.50 (apparent t, J =5.2 Hz, 1 H), 3.35(apparent t, J=5.5 Hz, 1 H), 3.26 (apparent t, J=5.2 Hz, 1 H), 2.68 (dq,J=12.8, 7.4 Hz, 1 H), 2.61 (dq, J=12.8, 7.5 Hz, 1 H), 2.71-2.58 (m, 2H), 2.51-2.44 (m, 1 H), 2.22 (apparent t, J=12.4 Hz, 1 H), 1.99-1.86 (m,3 H), 1.81 (apparent qt, J=7.1, 2.6 Hz, 1 H), 1.72 (br d, J=12.7 Hz, 1H), 1.62-1.57 (m, 1 H), 1.61 (s, 3 H), 1.56-1.48 (m, 1 H), 1.38 (ddd,J=13.5, 12.3, 1.4 Hz, 1 H), 1.27 (apparent t, J=7.4 Hz, 3 H), 1.03 (d,J=6.9 Hz, 3 H), 1.02 (d, J=6.8 Hz, 3 H), 0.95-0.92 (m, 9 H), 0.93 (s, 9H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.86 (s, 9 H), 0.74 (d, J=8.0 Hz, 3H), 0.73 (d, J=7.0 Hz, 3 H), 0.08 (s, 6 H), 0.05 (s, 3 H), 0.024 (s, 3H), 0.020 (s, 3 H), 0.012 (s, 3 H), 0.009 (s, 3 H), 0.006 (s, 3 H); ¹³ CNMR (125 MHZ, CDCl₃) d 159.4, 134.4, 132.3, 131.7, 130.9, 130.4, 129.3,114.0, 86.3, 80.9, 80.4, 77.6, 76.5, 75.3, 74.2, 65.6, 65.5, 55.3, 42.6,41.9, 40.0, 37.6, 37.0, 36.8, 35.9, 35.2, 34.5, 26.30, 26.27, 25.9,25.8, 25.1, 23.2, 18.53, 18.47, 18.13, 18.07, 17.1, 16.6, 15.7, 15.6,14.4, 13.6, 11.6, 11.4, -2.8, -3.2, -3.4, -3.6, -4.2, -4.5, -4.9; highresolution mass spectrum (FAB, NBA) m/z 1173.7859 (M+Na)⁺ ; calcd forC₆₃ H₁₂₂ O₈ SSi₄ Na: 1173.7835!.

EXAMPLE 45 Aldehyde (-)-56

A solution of alcohol (-)-55 (13.8 mg, 0.0120 mmol) and Et₃ N (42 μL,0.30 mmol) in CH₂ Cl₂ (200 μL) was cooled to 0° C. and treated withSO₃.pyridine (40 mg, 0.251 mmol) in DMSO (600 μL). After 45 min at 0°C., the mixture was diluted with ethyl acetate (30 mL), washed withaqueous NaHSO₄ (1.0M, 30 mL), brine (2×30 mL), dried over MgSO₄,filtered and concentrated. Pipette flash chromatography (3% ethylacetate/hexane) afforded (-)-56 (13.2 mg, 96% yield) as a colorless oil:α!²³ _(D) -32.1° (c 1.40, CHCl₃); IR (CHCl₃) 2960 (s), 2935 (s), 2880(m), 1720 (m), 1610 (m), 1512 (m), 1470 (m), 1460 (m), 1387 (m), 1380(m), 1360 (m), 1340 (m), 1320 (m), 1300 (m), 1250 (s), 1110 (s), 1098(s), 1080 (s), 1048 (s), 1002 (m), 988 (m), 965 (m), 950 (m), 935 (m),835 (s) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 9.78 (d, J=2.5 Hz, 1 H), 7.20(d, J=8.6 Hz, 2 H), 6.85 (d, J=8.7 Hz, 2 H), 5.27 (dd, J=11.1, 7.8 Hz, 1H), 5.19 (apparent t, J=10.4 Hz, 1 H), 5.10 (d, J=10.0 Hz, 1 H), 5.05(d, J=2.1 Hz, 1 H), 4.67 (apparent t, J=8.9 Hz, 1 H), 4.45 (apparent s,2 H), 3.78 (s, 3 H), 3.68 (apparent t, J=10.2 Hz, 1 H), 3.58-3.56 (m, 2H), 3.51 (apparent t, J=2.6 Hz, 1 H), 3.25 (apparent t, J=5.2 Hz, 1 H),2.73 (dqd, J=7.1, 6.0, 2.6 Hz, 1 H), 2.70-2.57 (m, 3 H), 2.51-2.44 (m, 1H), 2.23 (apparent t, J=12.4 Hz, 1 H), 1.98-1.85 (m, 2 H), 1.81(apparent qt, J=7.1, 2.6 Hz, 1 H), 1.67 (br d, J=13.0 Hz, 1 H), 1.60 (s,3 H), 1.62-1.50 (m, 2H), 1.37 (ddd, J=13.8, 10.4, 1.5 Hz, 1 H), 1.26(apparent t, J=7.4 Hz, 3 H), 1.10 (d, J=7.0 Hz, 3 H), 1.02 (d, J=7.0 Hz,3 H), 0.938 (d, J=7.1 Hz, 3 H), 0.932 (d, J=7.8 Hz, 3 H), 0.919 (s, 9H), 0.918 (d, J=6.6 Hz, 3 H), 0.90 (s, 9 H), 0.88 (s, 9 H), 0.86 (s, 9H), 0.732 (d, J=6.7 Hz, 3 H), 0.726 (d, J=6.8 Hz, 3 H), 0.07 (s, 3 H),0.053 (s, 3 H), 0.047 (s, 3 H), 0.02 (s, 6 H), 0.009 (s, 3 H), 0.005 (s,6 H); ¹³ C NMR (125 MHZ, CDCl₃) d 204.6, 159.3, 134.4, 132.3, 131.8,130.8, 130.3, 129.1, 128.3, 113.8, 82.6, 80.9, 80.4, 76.5, 74.5, 74.2,65.5, 55.3, 49.5, 42.5, 41.9, 40.3, 37.1, 36.8, 35.4, 34.9, 34.4, 26.3,26.2, 25.9, 25.8, 25.1, 23.2, 18.49, 18.45, 18.12, 18.07, 17.0, 16.6,15.6, 14.4, 13.3, 12.1, 11.6, 11.4, -2.8, -3.3, -3.4, -3.7, -4.2, -4.5,-4.9, -5.0; high resolution mass spectrum (FAB, NBA) m/z 1171.7670(M+Na)⁺ ; calcd for C₆₃ H₁₂₀ O_(hd) 8 SSiNa: 1171.7676!.

EXAMPLE 46 Tetraene (-)-57

A solution of Ph₂ PCH₂ CH═CH₂ (40 μL, 0.19 mmol) in THF (1.0 mL) wascooled to -78° C. and t-BuLi (1.7M in pentane, 72.0 μL, 0.122 mmol) wasadded. The mixture was stirred at 0° C. for 30 min, recooled to -78° C.and treated with Ti(OiPr)₄ (45 μL, 0.15 mmol). After 30 min, a cold(-78° C.) solution of the aldehyde (-)-56 (30.2 mg, 0.0262 mmol) in THF(1.0 mL) was introduced via cannula, and the resultant mixture wasstirred for 10 min at -78° C. and 1 h at 0° C. MeI (20 μL, 0.32 mmol)was then added, and the reaction was maintained at 0° C. for 30 min,warmed to room temperature, protected from light with aluminum foil, andstirred overnight. The reaction mixture was diluted with ether (30 mL),washed with aqueous NaHSO₄ (1.0M), brine (30 mL each), dried over MgSO₄,filtered and concentrated. Flash chromatography (2% ethylacetate/hexane) gave a 16:1 mixture of Z/E isomers (20.0 mg, 70% yield)as an oil. Pipette flash chromatography (20% benzene/hexane) furnishedthe Z-olefin (-)-57 as a colorless oil: α!²³ _(D) -57.2° (c 2.56,CHCl₃); IR (CHCl₃) 3015 (m), 2960 (s), 2940 (s), 2900 (m), 2885 (m),2860 (s), 1613 (w), 1515 (m), 1475 (m), 1465 (m), 1390 (w), 1380 (w),1360 (w), 1250 (s), 1110 (m), 1100 (m), 1080 (m), 1050 (s), 1003 (m),963 (w), 950 (w), 835 (s), 800 (m), 790 (m), 770 (m), 700 (w), 690 (w),670 (w), 655 (w) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.25 (d, J=8.2 Hz, 2H), 6.84 (d, J=8.7 Hz, 2 H), 6.57 (dddd, J=16.8, 11.0, 11.0, 0.7 Hz, 1H), 6.00 (apparent t, J=11.1 Hz, 1 H), 5.55 (apparent t, J=10.5 Hz, 1H), 5.26 (dd, J=11.2, 7.8 Hz, 1 H), 5.20-5.16 (m, 2 H), 5.09 (d, J=10.1Hz, 1 H), 5.05 (d, J=2.2 Hz, 1 H), 5.03 (d, J=10.0 Hz, 1 H), 4.67(apparent t, J=9.1 Hz, 1 H), 4.49 (ABq, J_(AB) =10.6 Hz, Δδ_(AB) =41.3Hz, 2 H), 3.78 (s, 3 H), 3.68 (apparent t, J=10.2 Hz, 1 H), 3.52(apparent t, J =2.6 Hz, 1 H), 3.43 (dd, J=4.8, 3.9 Hz, 1 H), 3.24-3.21(m, 2 H), 3.01-2.94 (m, 1 H), 2.67 (dq, J=12.8, 7.4 Hz, 1 H), 2.61 (dq,J=12.8, 7.5 Hz, 1 H), 2.71-2.57 (m, 1 H), 2.46-2.39 (m, 1 H), 2.00(apparent t, J=12.4 Hz, 1 H), 1.83-1.73 (m, 3 H), 1.64 (br d, J=14.0 Hz,1 H), 1.62-1.52 (m, 2 H), 1.55 (d, J=0.5 Hz, 3 H), 1.36 (ddd, J=13.7,10.8, 1.5 Hz, 1 H), 1.26 (d, J=7.4 Hz, 3 H), 1.25 (d, J=7.4 Hz, 3 H),1.08 (d, J=6.8 Hz, 3 H), 0.98 (d, J=6.8 Hz, 3 H), 0.94 (d, J=7.1 Hz, 3H), 0.93 (s, 9 H), 0.90 (S, 9 H), 0.89 (s, 9 H), 0.89-0.86 (m, 3 H),0.86 (s, 9 H), 0.73 (d, J=6.8 Hz, 3 H), 0.70 (d, J=6.7 Hz, 3 H), 0.08(s, 6 H), 0.05 (s, 3 H), 0.02 (s, 3 H), 0.013 (s, 3 H), 0.010 (s, 6 H),-0.02 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 159.1, 134.5, 134.3, 132.2,131.9, 131.8, 131.2, 129.13, 129.07, 117.6, 113.7, 84.6, 80.9, 80.5,76.5, 75.0, 74.2, 65.5, 55.3, 42.5, 41.9, 40.2, 37.2, 36.1, 35.4, 35.3,34.5, 29.7, 26.3, 26.0, 25.9, 25.1, 23.1, 18.7, 18.6, 18.5, 18.14,18.09, 17.0, 16.8, 15.6, 14.8, 14.4, 11.6, 10.6, -2.8, -3.2, -3.3, -3.6,-4.2, -4.5, -4.90, -4.93; high resolution mass spectrum (FAB, NBA) m/z1195.8001 (M+Na)⁺ ; calcd for C₆₆ H₁₂₄ O₇ SSi₄ Na: 1195.8042!.

EXAMPLE 47 Lactone (-)-58

A solution of diene (-)-57 (7.0 mg, 0.00597 mmol) in THF/CH₃ CN (2:1,1.50 mL) was treated with pH 7.0 phosphate buffer (500 μL) and HgCl₂(215 mg). The suspension was stirred at room temperature for 40 min,diluted with ether (30 mL), washed with brine (2×30 mL), dried overMgSO₄, filtered and concentrated. Pipette flash chromatography (5% ethylacetate/hexane) provided a mixture of lactols as a colorless oil whichwas further treated with DMSO (1.0 mL) and Ac₂ O (200 mL) at roomtemperature for 2 days. The mixture was diluted with ether (30 mL),washed with saturated NaHCO₃ (30 mL), brine (30 mL), dried over MgSO₄,filtered and concentrated. Pipette flash chromatography (20% ethylacetate/hexane) provided (-)-58 (5.5 mg, 82% yield from (-)-57) as acolorless oil: α!²³ _(D) -31.6 (c 0.23, CHCl₃); IR (CHCl₃) 3015 (m),2960 (s), 2930 (s), 2880 (m), 2855 (m), 1725 (m), 1610 (w), 1510 (w),1460 (m), 1385 (m), 1373 (m), 1360 (m), 1300 (w), 1250 (s), 1230 (m),1200 (m), 1170 (m), 1120 (m), 1097 (m), 1060 (m), 1045 (s), 1020 (m),1003 (m), 980 (w), 955 (w), 930 (w), 905 (w), 867 (m), 835 (s), 800 (m),695 (m), 670 (m), 660 (m) cm⁻¹ ; ¹ H NMR (500 MHZ, CDCl₃) d 7.25 (d,J=9.0 Hz, 2 H), 6.84 (d, J=8.7 Hz, 2 H), 6.57 (ddd, J=16.7, 10.6, 10.6Hz, 1 H), 6.00 (apparent t, J=11.0 Hz, 1 H), 5.55 (apparent t, J 10.5Hz, 1 H), 5.26 (dd, J=11.1, 7.9 Hz, 1 H), 5.19 (dd, J=15.4, 1.4 Hz, 1H), 5.18 (apparent t J=10.1 Hz, 1 H), 5.10 (d, J=10.2 Hz, 1 H), 5.01 (d,J=10.0 Hz, 1 H), 4.75 (apparent t, J=9.2 Hz, 1 H), 4.50 (ddd, J=10.5,1.3, 1.3 Hz, 1 H), 4.50 (ABq, J_(AB) =10.6 Hz, Δδ_(AB) =42.6 Hz, 2 H),3.78 (s, 3 H), 3.60 (apparent t, J=2.4 Hz, 1 H), 3.42 (dd, J=5.1, 3.7Hz, 1 H), 3.23 (dd, J=7.5, 3.7 Hz, 1 H), 3.20 (apparent t, J=5.4 Hz, 1H), 3.01-2.94 (m, 1 H), 2.60 (qd, J=7.7, 2.6 Hz, 1 H), 2.62-2.55 (m, 1H), 2.45-2.38 (m, 1 H), 1.98 (apparent t, J=12.3 Hz, 1 H), 1.84-1.67 (m,3 H), 1.63 (br d, J=13.2 Hz, 1H), 1.52 (s, 3 H), 1.55-1.48 (m, 1 H),1.20 (d, J=7.6 Hz, 3 H), 1.09 (d, J=6.8 Hz, 3 H), 0.98 (d, J=6.8 Hz, 3H), 0.93 (apparent d, J=6.7 Hz, 6 H), 0.93 (s, 9 H), 0.89 (s, 9 H), 0.86(s, 9 H), 0.85 (s, 9 H), 0.84 (d, J=6.8 Hz, 3 H), 0.69 (d, J=6.7 Hz, 3H), 0.085 (s, 3 H), 0.079 (s, 3 H), 0.051 (s, 3 H), 0.046 (s, 3 H),0.042 (s, 3 H), 0.029 (s, 3 H), 0.028 (s, 3 H), -0.02 (s, 3 H); ¹³ C NMR(125 MHZ, CDCl₃) d 173.2, 159.1, 134.4, 133.4, 132.4, 132.2, 131.9,131.3, 131.2, 129.11, 129.09, 117.6, 113.7, 84.6, 80.5, 76.9, 75.0,74.9, 64.6, 55.3, 44.1, 42.7, 40.1, 37.5, 36.0, 35.44, 35.37, 35.2,34.2, 26.31, 26.28, 25.9, 25.7, 23.0, 18.7, 18.6, 18.4, 18.1, 18.0,17.1, 16.5, 16.4, 14.9, 14.1, 10.5, -3.0, -3.2, -3.3, -4.3, -4.4, -4.5,-4.8, -4.9; high resolution mass spectrum (FAB, NBA) m/z 1149.7836(M+Na)⁺ ; Calcd for C₆₄ H₁₁₈ O₈ Si₄ Na: 1149.7802!.

EXAMPLE 48 Alcohol (-)-59

A solution of (-)-58 (4.0 mg, 0.00355 mmol) in CH₂ Cl₂ (500 μL) wastreated with H₂ O (50 μL) and DDQ (3.0 mg, 0.0132 mmol) at 0° C. After 1h, the mixture was diluted with ethyl acetate (30 mL), washed with brine(3×30 mL), dried over MgSO₄, filtered and concentrated. Pipette flashchromatography (2% ethyl acetate/hexane) provided (-)-59 (3.4 mg, 95%yield) as a colorless oil: α!²³ _(D) -20° (c 0.34, CHCl₃); IR (film,CHCl₃ on NaCl plate) 3500 (w, br), 2960 (s), 2930 (s), 2890 (s), 2855(s), 1740 (m), 1460 (m), 1405 (m), 1380 (m), 1360 (s), 1253 (m), 1220(m), 1120 (s), 1093 (s), 1075 (s), 1045 (s), 1022 (s), 1002 (m), 980(m), 933 (m), 902 (m), 833 (s), 808 (m), 770 (s), 663 (m) cm⁻¹ ; ¹ H NMR(500 MHZ, CDCl₃) d 6.61 (ddd, J=16.8, 10.9, 10.9 Hz, 1 H), 6.13(apparent t, J=11.0 Hz, 1 H), 5.32 (apparent t, J=10.5 Hz, 1 H), 5.28(dd, J=11.1, 7.9 Hz, 1 H), 5.24-5.21 (m, 1 H), 5.19 (apparent t, J=10.3Hz, 1 H), 5.14 (d, J=10.2 Hz, 1 H), 5.06 (d, J=10.0 Hz, 1 H), 4.76(apparent t, J=9.3 Hz, 1 H), 4.50 (apparent t, J=9.9 Hz, 1 H), 3.62(apparent t, J=2.4 Hz, 1 H), 3.60 (dd, J=5.5, 3.4 Hz, 1 H), 3.32 (br d,J=5.3 Hz, 1 H), 3.24 (apparent t, J=5.1 Hz, 1 H), 2.79 (ddq, J=9.9, 6.7,6.7 Hz, 1 H), 2.60 (qd, J=7.6, 2.7 Hz, 1 H), 2.63-2.57 (m, 1 H),2.50-2.45 (m, 1 H), 2.16 (apparent t, J=12.3 Hz, 1 H), 1.90-1.77 (m, 3H), 1.75-1.69 (m, 2 H), 1.57 (s, 3 H), 1.60-1.50 (m, 1 H), 1.20 (d,J=7.6 Hz, 3 H), 0.96 (d, J=6.8 Hz, 3 H), 0.95 (d, J=6.6 Hz, 3 H),0.95-0.93 (m, 6 H), 0.91 (s, 9 H), 0.89 (s, 9 H), 0.89-0.84 (m, 3 H),0.87 (s, 9 H), 0.85 (s, 9 H), 0.73 (d, J=6.8 Hz, 3 H), 0.07 (apparent s,6 H), 0.052 (s, 3 H), 0.051 (s, 3 H), 0.04 (apparent s, 6 H), 0.03 (s, 3H), -0.01 (s, 3 H); ¹³ C NMR (125 MHZ, CDCl₃) d 173.3, 134.7, 133.5,132.5, 132.1, 132.0, 131.5, 131.0, 118.4, 80.5, 78.8, 76.4, 74.9, 64.7,44.1, 42.7, 38.0, 37.4, 36.3, 36.1, 35.2, 35.1, 34.2, 26.3, 26.2, 25.9,25.7, 23.2, 18.5, 18.1, 18.0, 17.3, 17.2, 16.4, 16.1, 14.1, 13.7, 9.4,-3.0, -3.3, -3.6, -4.34, -4.36, -4.5, -4.8; high resolution massspectrum (FAB, NBA) m/z 1029.7273 (M+Na)⁺ ; calcd for C₅₆ H₁₁₀ O₇ Si₄Na: 1029.7226!.

EXAMPLE 49 Carbamate (-)-60

A solution of alcohol (-)-59 (2.2 mg, 0.00219 mmol) in CH₂ Cl₂ (500 μL)was treated with Cl₃ CON═C═O (20 μL, 0.168 mmol) at room temperature.After 30 min, the mixture was diluted with regular CH₂ Cl₂ (2.0 mL) andtreated with neutral Al₂ O₃ (500 mg). The mixture was stirred at roomtemperature for 2 h, filtered through a short silica plug, andconcentrated. Pipette flash chromatography (10% ethyl acetate/hexane)provided (-)-60 (1.9 mg, 83% yield) as a colorless oil: α!²³ _(D) -37°(c 0.19, CHCl₃); IR (film, CHCl₃ on NaCl plate) 3510 (m), 3360 (m, br),3180 (m), 2960 (s), 2930 (s), 2880 (s), 2855 (s), 1730 (s, br), 1596(m), 1460 (s), 1385 (s), 1362 (s), 1325 (m), 1255 (s), 1220 (m), 1100(s), 1043 (s), 983 (m), 937 (m), 904 (m), 832 (s), 770 (s), 663 (m) cm⁻¹; ¹ H NMR (500 MHZ, CDCl₃) d 6.58 (dddd, J=16.8, 10.6, 10.6, 0.7 Hz, 1H), 6.01 (apparent t, J=11.0 Hz, 1 H), 5.36 (apparent t, J=10.4 Hz, 1H), 5.27 (dd, J=11.1, 7.9 Hz, 1 H), 5.22-5.16 (m, 2 H), 5.12 (d, J=10.1Hz, 1 H), 5.03 (d, J=10.0 Hz, 1 H), 4.76 (apparent t, J=9.2 Hz, 1 H),4.71 (apparent t, J=6.1 Hz, 1 H), 4.50 (ddd, J=10.5, 10.5, 1.3 Hz, 1 H),4.44 (br s, 2 H), 3.62 (apparent t, J=2.4 Hz, 1 H), 3.42 (apparent t,J=4.5 Hz, 1 H), 3.22 (apparent t, J=5.3 Hz, 1 H), 2.98 (ddq, J=10.1,6.6, 6.6 Hz, 1 H), 2.60 (qd, J=7.6, 2.7 Hz, 1 H), 2.63-2.55 (m, 1 H),2.48-2.41 (m, 1 H), 2.09 (apparent t, J=12.4 Hz, 1 H), 1.93-1.88 (m, 1H), 1.87-1.77 (m, 2 H), 1.71 (ddd, J=14.1, 10.8, 1.6 Hz, 1 H), 1.67 (brd, J=13.7 Hz, 1 H), 1.56 (apparent s, 3 H), 1.55-1.50 (m, 1 H), 1.21 (d,J=7.6 Hz, 3 H), 0.98 (d, J=6.8 Hz, 3 H), 0.95 (d, J=7.0 Hz, 3 H), 0.94(d, J=7.5 Hz, 3 H), 0.918 (d, J=6.8 Hz, 3 H), 0.915 (s, 9 H), 0.89 (s, 9H), 0.86 (s, 9 H), 0.853 (d, J=6.4 Hz, 3 H), 0.847 (s, 9 H), 0.70 (d,J=6.8 Hz, 3 H), 0.09 (s, 3 H), 0.07 (s, 3 H), 0.053 (s, 3 H), 0.051 (s,3 H), 0.040 (s, 3 H), 0.037 (s, 3 H), 0.03 (s, 3 H), -0.02 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 173.3, 156.9, 133.6, 133.5, 132.4, 132.1,131.9, 131.4, 129.8, 118.0, 80.5, 78.9, 74.9, 64.6, 44.2, 42.7, 37.8,37.4, 36.0, 35.3, 35.2, 34.5, 34.2, 26.3, 26.2, 25.9, 25.7, 23.0, 18.5,18.4, 18.1, 18.0, 17.5, 17.1, 16.44, 16.38, 14.1, 13.7, 10.1, -3.0,-3.4, -3.6, -4.4, -4.5, -4.8; high resolution mass spectrum (FAB, NBA)m/z 1072.7264 (M+Na)⁺ ; calcd for C₅₇ H₁₁₁ NO₈ Si₄ Na: 1072.7283!.

EXAMPLE 50 Discodermolide (-)-1!

A solution of olefin (-)-60 (5.8 mg, 5.5 mmol) in 48% HF--CH₃ CN (1:9,1.0 mL) was stirred at room temperature for 12 h, then quenched withsaturated aqueous NaHCO₃ (5.0 mL). The mixture was extracted with ethylacetate (3×10 mL). The combined organic extracts were washed with brine(5.0 mL), dried over MgSO₄, filtered and concentrated. Pipette flashchromatography (gradient elution, 1:30 to 1:6 MeOH/CHCl₃) provided (-)-1(2.0 mg, 60% yield) as a white amorphous solid: α!²³ _(D) -16° (c 0.03,MeOH); IR (CHCl₃) 3690 (w), 3620 (w), 3540 (w), 3430 (w), 3020 (s), 2975(m), 2935 (m), 1740 (m), 1590 (w), 1540 (w), 1520 (w), 1467 (w), 1430(w), 1385 (m), 1330 (w), 1233 (s), 1210 (s), 1100 (w), 1045 (m), 1033(m), 975 (w), 930 (m), 910 (w), 793 (m), 777 (m), 765 (m), 750 (m), 705(m), 687 (m), 670 (m), 660 (m), 625 (w) cm7¹ ; ¹ H NMR (500 MHZ, CDCl₃)d 6.60 (dddd, J=16.8, 8.4, 8.4, 0.8 Hz, 1 H), 6.02 (apparent t, J=11.1Hz, 1 H), 5.51 (dd, J=11.2, 7.9 Hz, 1 H), 5.42 (ddd, J=10.6, 10.6, 0.6Hz, 1 H), 5.34 (apparent t, J=10.4 Hz, 1 H), 5.20 (dd, J=16.9, 1.9 Hz, 1H), 5.16 (d, J=10.0 Hz, 1 H), 5.11 (d, J=10.1 Hz, 1 H), 4.77-4.69 (m, 1H), 4.70 (dd, J=7.3, 4.2 Hz, 1 H), 4.60 (ddd, J=10.0, 10.0, 2.4 Hz, I1H), 4.56 (br s, 2 H), 3.73 (m, 1 H), 3.28 (m, 1 H), 3.18 (dd, J=6.8, 4.8Hz, 1 H), 2.98 (ddq, J=10.1, 6.9, 6.9 Hz, 1 H), 2.78 (ddq, J=9.8, 6.8,6.8 Hz, 1 H), 2.66 (qd, J=7.3, 4.6 Hz, 1 H), 2.60-2.55 (m, 1 H),2.10-1.80 (m, 10 H), 1.69 (ddd, J=14.4, 10.3, 3.1 Hz, 1 H), 1.64 (d,J=1.3 Hz, 3 H), 1.30 (d, J=7.4 Hz, 3 H), 1.06 (d, J=6.9 Hz, 3 H), 1.00(d, J=6.8 Hz, 3 H), 0.99 (d, J=6.7 Hz, 3 H), 0.97 (d, J=6.8 Hz, 3 H),0.94 (d, J=6.8 Hz, 3 H), 0.82 (d, J=6.3 Hz, 3 H); ¹³ C NMR (125 MHZ,CDCl₃) d 173.6, 157.0, 134.4, 133.7, 133.4, 132.9, 132.2, 129.9, 129.8,117.9, 79.1, 78.9, 77.9, 75.7, 73.2, 64.4, 43.1, 41.0, 37.4, 36.1, 36.0,35.8, 35.3, 34.8, 33.1, 23.3, 18.4, 17.4, 15.6, 15.5, 13.7, 12.5, 9.0;high resolution mass spectrum (FAB, NBA) m/z 616.3840 (M+Na)⁺ ; calcdfor C₃₃ H₅₅ NO₈ Na: 616.3826!.

EXAMPLE 51 (FIGS. 16 and 17)

A. Tosylate 101

A solution of diene 16 (see, Smith, et al., J. Am. Chem. Soc. 1995, 117,12011) (1.15 g, 1.0 mmol) in anhydrous pyridine (10 mL) at 0° C. istreated with p-toluenesulfonyl chloride (286 mg, 1.5 mmol). The mixtureis allowed to warm to room temperature for 4-6 h. The pyridine isremoved in vacuo and the residue is purified by flash chromatography toafford tosylate 101.

B. Arene 102

Phenyllithium (2.7 mL, 1.8M in cyclohexane-ether (70:30)) is addeddropwise to a solution of copper (I) iodide (460 mg, 2.4 mmol) inanhydrous diethyl ether (5 mL) at 0° C. To the resultant mixture isadded a solution of tosylate 101 (780 mg, 0.6 mmol) in ether (5 mL) andthe resultant mixture is warmed to room temperature with stirring. After4 h, saturated aqueous ammonium chloride (20 mL) is added. The layersare separated and the aqueous layer is extracted with ethyl acetate. Thecombined organics are dried over magnesium sulfate and concentrated invacuo. The residue is purified by flash chromatography to afford 102.

C. Lactol 103

To a solution of 102 (120 mg, 0.1 mmol) in tetrahydrofuran-acetonitrile(15 mL, 2:1) is added phosphate buffer (pH 7, 5 mL) and mercury (II)chloride (272 mg, 1.0 mmol). The resultant mixture is stirred 1 h atroom temperature. The reaction mixture is diluted with ether (100 mL)and washed with saturated aqueous brine (2×50 mL), dried over magnesiumsulfate and concentrated in vacuo. The residue is purified by flashchromatography to afford 103 as a mixture of α and β anomers.

D. Lactone 104

To a solution of 103 (84 mg, 0.070 mmol) in dimethyl sulfoxide (10 mL)is added acetic anhydride (2 mL). After 2 days at room temperature, themixture is diluted with ether (100 mL) and washed with saturated aqueoussodium bicarbonate (50 mL), saturated aqueous brine (50 mL)), dried overmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 104.

E. Alcohol 105

To a solution of 104 (56 mg, 0.050 mmol) in dichloromethane (3 mL) at 0°C. is added water (50 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(52 mg, 0.018 mmol). After 1 h, the reaction mixture is diluted withethyl acetate (50 mL), washed with saturated aqueous brine (3×25 mL),dried over magnesium sulfate and concentrated in vacuo. The residue ispurified by flash chromatography to afford 105.

F. Carbamate 106

To a solution of 105 (10 mg, 0.010 mmol) in dichloromethane (2 mL) isadded trichloroacetyl isocyanate (0.12 mL, 1.00 mmol). After 30 min, thereaction mixture is diluted with dichloromethane (4 mL) and neutralalumina (1 g) is added. The resultant suspension is stirred anadditional 4 h. The reaction mixture is filtered and the concentratedfiltrate is chromatographed on silica gel to afford 106.

G. Tetrol 107

A solution of 106 (10 mg, 0.0096 mmol) in 48% hydrofluoricacid-acetonitrile (1:9, 2 mL) is stirred at ambient temperature. After12 h, saturated aqueous sodium bicarbonate (25 mL) is added and themixture is extracted with ethyl acetate (3×20 mL). The combined organicsare dried over magnesium sulfate and concentrated in vacuo. The residueis purified by flash chromatography to afford 107.

EXAMPLE 52 (FIGS. 18-20)

A. Alcohol 203

To a slurry of powdered 4-Å molecular sieves (2.0 g) in 100 mL ofanhydrous toluene is added boronate 202 (see, Roush, et al., J. Am.Chem. Soc. 1990, 112, 6348) (170 mL, 1.0M in toluene). The resultantsolution is stirred 10 min at room temperature and then cooled to -78°C. A solution of aldehyde 201 (see, Solladie, et al., Tetrahedron Lett.1987, 28, 797) (113 mmol) in toluene (100 mL) is added over a 2 hperiod, after which the reaction is maintained at -78° C. for 10 h.Excess ethanolic sodium borohydride (ca. 0.75 g/10 mL) is added and thereaction mixture is warmed to 0° C. Aqueous 1N sodium hydroxide (300 mL)is added and the mixture is stirred vigorously for 2 h. The layers areseparated and the aqueous layer is extracted with ether (5×300 mL). Thecombined organics are dried over potassium carbonate and concentrated invacuo. The residue is purified by flash chromatography to afford 203.

B. Bis-silyl ether 204

A solution of 203 (75 mmol) in dimethylformamide (150 mL) is cooled to0° C. and treated with imidazole (150 mmol) and tert-butyldimethylsilylchloride (100 mmol). The resultant solution is warmed to roomtemperature. After 12 h, the reaction mixture is poured into 1500 mL ofwater and extracted with ether (3×200 mL). The ethereal extracts arewashed with water (2×50 mL) and saturated aqueous brine (50 mL), driedover magnesium sulfate and concentrated in vacuo. The residue ispurified by flash chromatography to afford 204.

C. Alcohol 205

A solution of 204 (20 mmol) in 500 mL of methanol is cooled to -78° C.and treated with a stream of ozone and oxygen until the colorlesssolution is converted into a steel blue one. The crude reaction mixtureis cautiously quenched with sodium borohydride (100 mmol) and theresultant solution is warmed to room temperature. After 3 h, the excesssodium borohydride is destroyed by the cautious addition of water. Themethanol is removed in vacuo and the residue is partitioned betweensaturated aqueous ammonium chloride (200 mL) and ethyl acetate (200 mL).The layers are separated and the aqueous layer is further extracted withethyl acetate (2×100 mL). The combined organics are dried over anhydrousmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 205.

D. Triethylsilyl ether 206

A solution of 205 (15 mmol) in dimethylformamide (30 mL) is cooled to 0°C. and treated with imidazole (30 mmol) and triethylsilyl chloride (20mmol). The resultant solution is warmed to room temperature. After 12 h,the reaction mixture is poured into 300 mL of water and extracted withether (3×40 mL). The ethereal extracts are washed with water (2×25 mL)and saturated aqueous brine (25 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by flash chromatographyto afford 206.

E. Alcohol 207

To a solution of 206 (6 mmol) in ethyl acetate-ethanol (8:1, 90 mL) isadded palladium on carbon (10% wet, 500 mg). The mixture is stirredunder hydrogen atmosphere for 3-6 h, then filtered and concentrated invacuo. The residue is purified by flash chromatography to afford 207.

F. Aldehyde 208

To a -10° C. solution of 207 (13 mmol) and triethylamine (50 mmol) indichloromethane (26 mL) is added a solution of sulfur trioxide-pyridine(39 mmol) in dimethyl sulfoxide (50 mL). The mixture is stirred 1 h atroom temperature and diluted with ether (150 mL). The organic phase iswashed with aqueous sodium bisulfate (1M, 100 mL), saturated aqueousbrine (4×100 mL), dried over magnesium sulfate, and concentrated invacuo. The residue is purified by flash chromatography to afford 208.

G. Wittig product 209

Phosphonium salt 15 (see, Smith, et al., J. Am. Chem. Soc. 1995, 117,12011) (0.2 mmol) is dissolved in anhydrous tetrahydrofuran (2 mL) andchilled to 0° C. A solution of sodium bis(trimethylsilyl)amide (0.2mmol, 1.0M in tetrahydrofuran) is added and the reaction mixture isstirred 30 min at 0° C. After cooling to -78° C., a solution of aldehyde208 (0.1 mmol) in tetrahydrofuran (2 mL) is added and the mixture isstirred 10 min at -78° C. and 2 h at room temperature. Saturated aqueousammonium chloride (2 mL) is added and the resultant mixture is extractedwith ether (3×20 mL). The ethereal layer is washed with water (2×25 mL)and saturated aqueous brine (25 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by flash chromatographyto afford 209.

H. Hydroxy diene 210

A -78° C. solution of 209 (0.05 mmol) in CH₂ Cl₂ (5 mL) is treated withdiisobutylaluminum hydride (0.5 mL, 1.0M in toluene). The resultantsolution is stirred 10 min at -78° C. and 30 min at 0° C. The reactionis quenched with a saturated solution of sodium potassium tartrate (50mL) and the mixture is diluted with ether (60 mL). The organic layer isseparated, dried over magnesium sulfate, and concentrated in vacuo. Theresidue is purified by flash chromatography to afford 210.

I. Aldehyde 211

To a -10° C. solution of 207 (1.3 mmol) and triethylamine (5.0 mmol) indichloromethane (3 mL) is added a solution of sulfur trioxide-pyridine(3.9 mmol) in dimethyl sulfoxide (5 mL). The mixture is stirred 1 h atroom temperature and diluted with ether (15 mL). The organic phase iswashed with aqueous sodium bisulfate (1M, 10 mL), saturated aqueousbrine (4×10 mL), dried over magnesium sulfate, and concentrated invacuo. The residue is purified by flash chromatography to afford 211.

J. Tetraene 212

A solution of diphenylallylphosphine (0.08 mL, 0.38 mmol) intetrahydrofuran (2 mL) is cooled to -78° C. and tert-butyllithium (0.14mL, 1.7M in pentane) is added. The mixture is warmed to 0° C. for 30min, then recooled to -78° C. and treated with titanium (IV)isopropoxide (0.30 mmol). After 30 min, aldehyde 211 (0.30 mmol) isintroduced as a solution in tetrahydrofuran (2 mL). The resultantsolution is stirred at -78° C. for 15 min and at 0° C. for 1 h. Methyliodide (0.64 mmol) is added, and the reaction is warmed to roomtemperature for 12 h. The reaction mixture is diluted with ether (60mL), washed with aqueous sodium bisulfate (30 mL, 1.0M), saturatedaqueous brine (30 mL), and is dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by flash chromatographyto afford 212.

K. Aldehyde 213

Oxalyl chloride (1.5 mmol) is added dropwise to a -78° C. solution ofdimethyl sulfoxide (3 mmol) in dichloromethane (4 mL). After 15 min, a-78° C. solution of 212 (1 mmol) in dichloromethane (2 mL) is added viacanula. After an additional 15 min, diisopropylethylamine (4.5 mmol) isadded and the reaction is gradually warmed to room temperature over 1 hand quenched with aqueous sodium bisulfate. The mixture is diluted withether (50 mL) and is washed with water (2×30 mL), saturated aqueousbrine (2×30 mL), is dried over magnesium sulfate and concentrated invacuo. The residue is purified by flash chromatography to afford 213.

L. Ester 214

To a -78° C. solution of (F₃ CCH₂ O)₂ POCH₂ CO₂ Et (2 mmol) and18-crown-6 (2.4 mmol) in tetrahydrofuran (5 mL) is added potassiumbis(trimethylsilyl)amide (2 mmol) in tetrahydrofuran All (2 mL). Theresultant solution is stirred 10 min at -78° C. and then treated withaldehyde 213 (1.2 mmol) in 4 mL of tetrahydrofuran. The reaction mixtureis warmed to 0° C. for 6-8 h and then quenched with saturated aqueousammonium chloride (10 mL). The aqueous layer is separated and extractedwith hexane (2×25 mL). The combined organics are dried over magnesiumsulfate and concentrated in vacuo. The residue is purified by flashchromatography to afford 214.

M. Alcohol 215

To a solution of 214 (0.050 mmol) in dichloromethane (3 mL) at 0° C. isadded water (50 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.018mmol). After 1 h, the reaction mixture is diluted with ethyl acetate (50mL), washed with saturated aqueous brine (3×25 mL), dried over magnesiumsulfate and concentrated in vacuo. The residue is purified by flashchromatography to afford 215.

N. Carbamate 216

To a solution of 215 (0.010 mmol) in dichloromethane (2 mL) is addedtrichloroacetyl isocyanate (1.00 mmol). After 30 min, the reactionmixture is diluted with dichloromethane (4 mL) and neutral alumina (1 g)is added. The resultant suspension is stirred an additional 4 h. Thereaction mixture is filtered and the concentrated filtrate ischromatographed on silica gel to afford 216.

O. Triol 217

A solution of 216 (0.010 mmol) in 480 hydrofluoric acid-acetonitrile(1:9, 2 mL) is stirred at ambient temperature. After 12 h, saturatedaqueous sodium bicarbonate (25 mL) is added and the mixture is extractedwith ethyl acetate (3×20 mL). The combined organics are dried overmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 217.

EXAMPLE 53 (FIGS. 21 and 22)

A. Hydroxy-oxazole 302

A solution of oxazole (3 mmol) in tetrahydrofuran (15 mL) is cooled to-78° C. and treated with n-BuLi (3 mmol) in hexane. (see, Hodges, etal., J. Org. Chem. 1991, 56, 449). After 30 min at -78° C., previouslyprepared (see, Smith, et al., J. Am. Chem. Soc. 1995, 117, 12011)aldehyde 301 (2 mmol) is added in tetrahydrofuran (10 mL) and thereaction mixture is gradually allowed to warm to room temperature. After18-24 h, the reaction is quenched by addition of saturated aqueousammonium chloride (25 mL). The aqueous layer is separated and extractedwith ether (3×25 mL). The combined organics are dried over magnesiumsulfate and concentrated in vacuo. The residue is purified by flashchromatography to afford 302.

B. Tosylate 303

A solution of 302 (1.0 mmol) in anhydrous pyridine (10 mL) at 0° C. istreated with p-toluenesulfonyl chloride (286 mg, 1.5 mmol). The mixtureis allowed to warm to room temperature for 4-6 h. The pyridine isremoved in vacuo and the residue is purified by flash chromatography toafford tosylate 303.

C. Reduction product 304

To a 0° C. solution of tosylate 303 (0.5 mmol) in tetrahydrofuran (2 mL)is added lithium triethylborohydride (2 mmol) as a solution intetrahydrofuran (1.0M). The resultant solution is warmed to roomtemperature for 2-4 h and then quenched with water (1 mL) and dilutedwith ether (25 mL). The ethereal layer is washed with saturated aqueousbrine (2×10 mL), dried over magnesium sulfate, and concentrated invacuo. The residue is purified by flash chromatography to afford 304.

D. Lactol 305

To a solution of 304 (0.1 mmol) in tetrahydrofuran-acetonitrile (15 mL,2:1) is added phosphate buffer (pH 7, 5 mL) and mercury (II) chloride(1.0 mol). The resultant mixture is stirred 1 h at room temperature. Thereaction mixture is diluted with ether (100 mL) and washed withsaturated aqueous brine (2×50 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by flash chromatographyto afford 305 as a mixture of α and β anomers.

E. Lactone 306

To a solution of 305 (0.070 mmol) in dimethyl sulfoxide (10 mL) is addedacetic anhydride (2 mL). After 2 days at room temperature, the mixtureis diluted with ether (100 mL) and washed with saturated aqueous sodiumbicarbonate (50 mL), saturated aqueous brine (50 mL), dried overmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 306.

F. Alcohol 307

To a solution of 306 (0.050 mmol) in dichloromethane (3 ML) at 0° C. isadded water (50 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.018mmol). After 1 h, the reaction mixture is diluted with ethyl acetate (50mL), washed with saturated aqueous brine (3×25 mL), dried over magnesiumsulfate and concentrated in vacuo. The residue is purified by flashchromatography to afford 307.

G. Carbamate 308

To a solution of 307 (0.010 mmol) in dichloromethane (2 mL) is addedtrichloroacetyl isocyanate (1.00 mmol). After 30 min, the reactionmixture is diluted with dichloromethane (4 mL) and neutral alumina (1 g)is added. The resultant suspension is stirred an additional 4 h. Thereaction mixture is filtered and the concentrated filtrate ischromatographed on silica gel to afford 308.

H. Tetrol 309

A solution of 308 (0.010 mmol) in 48% hydrofluoric acid-acetonitrile(1:9, 2 mL) is stirred at ambient temperature. After 12 h, saturatedaqueous sodium bicarbonate (25 mL) is added and the mixture is extractedwith ethyl acetate (3×20 mL). The combined organics are dried overmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 309.

EXAMPLE 54

As shown in FIG. 23, a solution of 402 (10.5 mg, 10.4 mmol) in 48%HF--CH₂ CN (1:9, 1.0 mL) is stirred at room temperature for 12 hr. Thereaction is quenched by saturated NaHCO₃ (5.0 mL). The mixture isextracted with ethyl acetate (3×10 mL). The combined organic phase isthen washed with brine (5.0 mL), dried over MgSO₄, concentrated invacuo. The residue is purified by flash chromatography to afford 401.

EXAMPLE 55 (FIG. 24)

A. PMB-ether 503

ZnCl₂ (1.32 g, 9.69 mmol) is dried at 160° C. under vacuum overnight andthen treated with a solution of iodide 502 (2.46 g, 9.59 mmol) in dryEt₂ O (50 mL). The mixture is stirred at room temperature until most ofthe ZnCl₂ is dissolved and then cooled to -78° C. t-BuLi (1.7M inpentane, 17.0 mL) is added over 30 min, and the resultant solution isstirred an additional 15 min, warmed to room temperature, and stirredfor 1 hr. The solution is added by cannula to a mixture of iodoolefin B(see, Smith, et al., J. Am. Chem. Soc. 1995, 117, 12011) (3.21 g, 6.19mmol) and Pd(PPh₃)₄ (364.2 mg, 0.315 mmol). The mixture is covered withaluminum foil, stirred overnight, and then diluted with ethylacetate(100 mL), washed with brine (2×100 mL), dried over MgSO₄,filtered and concentrated in vacuo. The residue is purified by flashchromatography to afford 503.

B. Phosphonium salt 504

A solution of alcohol 503 (1.70 g, 3.26 mmol) in CH₂ Cl₂ (28 mL) iscooled to 0° C. and treated with water (1.3 mL) and2,3-dichloro-5,6-dicyano-1,4-benzoquinone (774 mg, 3.41 mmol). Themixture is stirred at 0° C. for 5 hr, diluted with CH₂ Cl₂ (20 mL),dried over MgSO₄, and filtered through a column of silica gel. Followingconcentration in vacuo, the residue is dissolved in ethanol (50 mL) atroom temperature, and excess sodium borohydride is added. After 30 min,the reaction is cooled to 0° C., quenched with saturated aqueous NH₄ Cl(50 mL), and concentrated. The residue is then dissolved in CH₂ Cl₂ (90mL), and the solution is washed with water, dried over MgSO₄, filteredand concentrated in vacuo. The residue is purified by flashchromatography to afford an alcohol

A solution of this alcohol (400 mg, 1.0 mmol) in dry benzene/ether (1:2,50 mL) is treated with triphenylphosphine (923 mg, 3.6 mmol) andimidazole (273 mg, 4.0 mmol). After all of the imidazole dissolved,iodine (761 mg, 3.0 mmol) is added with vigorous stirring of thereaction mixture. The mixture is stirred 2 h further and then treatedwith triethylamine (4 mL). The resultant solution is diluted with CH₂Cl₂ (50 mL) and washed with saturated aqueous Na₂ S₂ O₃ (100 mL),saturated aqueous NaHCO (100 mL), and brine (2×100 mL). The organicphase is dried over MgSO₄, filtered and concentrated in vacuo.Filtration though silica gel to remove triphenylphosphine oxide, affordsan iodide. The iodide was mixed with diisopropylethylamine (0.6 mL, 3.44mmol) and triphenylphosphine (4.94 g, 18.8 mmol). The mixture is heatedat 80° C. for 24 hr, cooled to room temperature, and washed withhexane(2×50 mL). The product is isolated by flash chromatography toafford 504.

C. Coupled product 505

Phosphonium salt 504 (386 mg, 0.5 mmol) is dried azeotropically with drybenzene and heated at 50° C. under vacuum for 3 hr before use. It isthen dissolved in tetrahydrofuran (3.0 mL). Sodiumbis(trimethylsilyl)amide (1.0M in tetrahydrofuran, 0.48 mL, 0.48 mmol)is added at -78° C., and the mixture is stirred for 25 min and thenrecooled to -78° C. A solution of aldehyde C (see, Smith, et al., J. Am.Chem. Soc. 1995, 117, 12011) (147 mg, 0.30 mmol) in tetrahydrofuran (1.5mL) is added, and the mixture is stirred for 10 min at -78° C., and 2 hrat room temperature. The reaction is quenched with saturated aqueous NH₄Cl (4.0 mL), the resultant mixture is extracted with ether (120 mL), andthe ether layer is washed with water (100 mL) and brine (100 mL), driedover MgSO₄, filtered and concentrated in vacuo. Flash chromatographyprovides olefin 505.

D. Lactone 506

To a solution of 505 (200 mg, 0.23 mmol) in tetrahydrofuran-acetonitrile(10 mL, 2:1) is added a phosphate buffer solution (pH=7.0, 3.3 mL), andHgCl₂ (1.3 g). The suspension is stirred at room temperature for 40 min,then diluted with ether (150 mL), washed with brine (2×70 mL), driedover MgSO₄, and concentrated in vacuo. Flash chromatography provides amixture of lactols as α/β anomers. This material is used directly in thenext oxidation: Under argon, to a solution of lactols indimethylsulfoxide (5.0 mL) is added acetic anhydride (1.0 mL). After 2days at room temperature, the mixture is diluted with ether (150 mL),washed with saturated NaHCO₃ (150 mL), brine (150 mL), dried over MgSO₄,and concentrated in vacuo. Flash chromatography affords a lactone. Asolution of the lactone (160 mg, 0.20 mmol) in methanol (4 mL) istreated with pyridinium p-toluenesulfonate (10 mg) and stirred at 40° C.for 30 min. The mixture is diluted with ether (80 mL) and washedsuccessively with saturated aqueous NaHCO₃ solution (90 mL) and brine(40 mL), and then dried over MgSO₄. The organic solution is concentratedin vacuo, and the residue is passed through a column of silica gel toprovide alcohol 506.

E. Acid 507

To a solution of alcohol 506 (140 mg, 0.19 mmol) in dimethylformamide(5.0 mL), is added pyridinium dichromate (210 mg, 0.55 mmol). Thereaction mixture is stirred at room temperature for 5 hr, and dilutedwith water (120 mL). The mixture is extracted with ether (3×15 mL). Theorganic solutions are combined and washed with brine (40 mL), and driedover MgSO₄. Then it is concentrated in vacuo to give a residue, which ispurified by flash chromatography to afford carboxylic acid 507.

F. Amino-amide 508

To a solution of 507 (60.0 mg, 78.1 mmol) and D-leucine hydrochloride(26.0 mg, 0.16 mmol) in CH₂ Cl₂ (3 mL) is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 23 mg,0.12 mmol) and 1-hydroxybenzotriazole (21.0 mg, 0.14 mmol), followed bydiisopropylamine (40 mL, 0.23 mmol). The mixture is stirred at roomtemperature overnight before addition of 5% KHSO₄ solution. Theresulting mixture is extracted with ethyl acetate (30 mL). The organiclayer is washed with brine (20 mL) and dried over MgSO₄, and thenconcentrated in vacuo. The residue is purified by column chromatographyto afford 508.

G. Analog 501

A solution of 508 (52 mg, 59 mmol) in 48% HF-acetonitrile(1:9, 1.0 mL)is stirred at room temperature for 12 hr. The reaction is quenched bysaturated NaHCO₃ (5.0 mL). The mixture is extracted with ethyl acetate(3×10 mL). The combined organic phase is then washed with brine (5.0mL), dried over MgSO₄, and concentrated in vacuo. Flash chromatographyprovides 501.

EXAMPLE 56 (FIG. 25)

A. Diene 603

Phosphonium salt 15 (98.0 mg, 0.092 mmol) is dried azeotropically withdry benzene and heated at 50° C. under vacuum for 3 hr before use. It isthen dissolved in tetrahydrofuran (0.7 mL). Sodiumbis(trimethylsilyl)amide (1.0M in tetrahydrofuran, 86 mL, 0.0855 mmol)is added at -78° C., and the mixture is stirred for 20 min and thenrecooled to -78° C. A solution of aldehyde 602 (13 mg, 60 mmol) intetrahydrofuran (300 mL) is added, and the mixture is stirred for 10 minat -78° C., and 2 hr at room temperature. The reaction is quenched withsaturated aqueous NH₄ Cl (1.0 mL). The resultant mixture is extractedwith ether (30 mL), and the ether layer is washed with water (30 mL) andbrine (30 mL), dried over MgSO₄, filtered and concentrated in vacuo.Flash chromatography provides the coupled product.

A solution of the olefin (39 mg, 44 mmol) in CH₂ Cl₂ is cooled to -78°C., diisobutylaluminum hydride (1.0M in toluene, 440 mL, 0.40 mmol) isadded dropwise over 5 min, and the resultant solution is stirred for 10min at -78° C. and 30 min at 0° C. The reaction is quenched with asaturated solution of Rochelle's salt, and the mixture is diluted withether (60 mL), washed with Rochelle solution, and brine (30 mL each),dried over MgSO₄, filtered and concentrated in vacuo. Flashchromatography provides alcohol 603.

B. Alkane 604

To a solution of alcohol 603 (82 mg, 0.93 mmol) in pyridine (1.5 mL) at0° C. is added p-toluenesulfonyl chloride (26.6 mg, 0.14 mmol) withstirring. After 3 hr, the reaction mixture is concentrated in vacuo. Theresidue is purified by column chromatography to give a tosylate. To asolution of this tosylate (94 mg, 0.91 mmol) in ether (5 mL) is addedlithium diisopropylcuprate (Pr₂ CuLi) (ca. 0.5M in ether, 10 mL, excess.The resultant solution is stirred for 8 hr and then quenched withsaturated aqueous solution of NH₄ Cl (50 mL). Stirring is continued foran additional 2 h. The organic phase is separated and washed with NH₄ Clsolution (20 mL), dried over MgSO₄, and concentrated in vacuo. Flashchromatography provides 604.

C. Enone 605

A solution of 604 (75 mg, 83 mmol) in methanol (2 mL) is treated withpyridinium p-toluenesulfonate (ca. 4 mg) and stirred at 40° C. for 30min. The mixture is diluted with ether (20 mL) and washed successivelywith saturated aqueous NaHCO₃ solution (25 mL) and brine (10 mL), andthen dried over MgSO₄. The organic solution is concentrated in vacuo,and the residue is passed through a column of silica gel to provide analcohol. To a solution of the alcohol (62.0 mg, 68.2 mmol) in benzene(2.0 mL) is added manganese(IV) oxide (100 mg, 1.15 mmol). Afterstirring for 8 h at room temperature, the reaction mixture is filteredthrough a pad of celite. The filtrate is concentrated in vacuo. Flashchromatography of the residue affords α,β-unsaturated ketone 605.

D. Triol 606

A solution of the α,β-unsaturated ketone 605 (45 mg, 56 mmol) in CH₂ Cl₂(2 mL) is cooled to 0° C. and treated with water (0.1 mL) and 2,3-dichloro-5, 6-dicyano-1, 4-benzoquinone (15 mg, 66 mmol). The mixtureis stirred at 0° C. for 5 hr, diluted with CH₂ Cl₂ (15 mL), dried overMgSO₄, and filtered through a column of silica gel. Followingconcentration in vacuo, the residue is used for next step withoutfurther purification. A solution of the crude alcohol in 48%HF-acetonitrile (1:9, 1.0 mL) is stirred at room temperature for 12 hr.The reaction is quenched by saturated NaHCO₃ (5.0 mL). The mixture isextracted with ethyl acetate (3×10 mL). The combined organic phase isthen washed with brine (5.0 mL), dried over MgSO₄, concentrated invacuo. The residue is purified by flash chromatography to afford 601.

EXAMPLE 57 (FIG. 26)

A. Alkane 702

To a solution of iodide A (300 mg, 0.54 mmol) in ether (5 mL) is addedlithium dibutylcuprate (Bu₂ CuLi) (ca. 0.5M in ether, 5.4 mL, excess) at-25° C. The resultant solution is stirred for 8 hr and then quenchedwith saturated aqueous NH₄ Cl (50 mL). Stirring is continued for another2 hr and the organic phase is separated. The organic solution is washedwith NH₄ Cl solution (20 mL) and dried over MgSO₄, and concentrated invacuo. Flash chromatography provides 702.

B. Alcohol 703

A solution of 702 (240 mg, 0.50 mmol) in CH₂ Cl₂ (6.0 mL) is cooled to-78° C. Diisobutylaluminum hydride (1.0M in toluene, 1.50 mL, 1.50 mmol)is added dropwise over 5 min. and the resultant solution is stirred for10 min at -78° C. and 30 min at 0° C. The reaction is quenched with asaturated solution of Rochelle's salt, and the mixture is diluted withether (60 mL), washed with Rochelle solution, and brine (30 mL each),dried over MgSO₄, filtered and concentrated in vacuo. Flashchromatography provides alcohol 703.

C. Iodide 704

A solution of alcohol 703 (210 mg, 0.44 mmol) in dry benzene/ether (1:2,5 mL) is treated with triphenylphosphine (420 mg, 1.6 mmol) andimidazole (123 mg, 1.8 mmol). After all of the imidazole dissolved,iodine (335 mg, 1.32 mmol) is added with vigorous stirring. The mixtureis stirred for 2 h and then treated with triethylamine (1.8 mL). Theresultant solution is diluted with CH₂ Cl₂ (22 mL) and washed withsaturated aqueous Na₂ S₂ O₃ (40 mL), saturated aqueous NaHCO₃ (40 mL),and brine (2×40 mL). The organic phase is dried over MgSO₄, filtered andconcentrated in vacuo. The residue is purified by flash chromatographyto afford iodide 704.

D. Phosphonium salt 705

The iodide 704 is mixed with triphenylphosphine (2.17 g, 8.27 mmol) andthe mixture is heated at 80° C. for 24 hr, cooled to room temperature,and washed with hexane (2×20 mL). Flash chromatography providesphosphonium salt 705.

E. Alkene 707

A solution of 705 (260 mg, 0.30 mmol) in tetrahydrofuran (6.0 mL) iscooled to -10° C. and a solution of n-butyl lithium (1.0M in hexane,0.29 mL, 0.29 mmol) is introduced dropwise over 5 min. The resultantsolution is stirred for 50 min at room temperature and then the mixtureis recooled to -78° C. and aldehyde 706 (39 mg, 0.3 mmol) is added asolution in tetrahydrofuran (1.5 mL). The mixture is stirred for 10 minat -78° C., and 1 hr at 0° C. The reaction is quenched with saturatedaqueous NH₄ Cl (1.0 mL) and the resultant mixture is extracted withether (30 mL). The ether layer is washed with water (30 mL) and brine(30 mL), dried over MgSO₄, filtered and concentrated in vacuo. Theresidue is purified by flash chromatography to afford olefin 707 (149mg, 85% yield).

F. Diol 708

Acetonide 707 (147 mg, 0.25 mmol) is dissolved in 80% aqueous aceticacid (2.5 mL) at room temperature. The reaction mixture is stirred for 4hr at room temperature and then diluted with water (20 mL). The mixtureis extracted with ethyl acetate (2×5 mL). The combined organic layersare washed with saturated NaHCO₃ solution, and brine (10 mL each), andthen dried over MgSO₄. The organic solution is concentrated in vacuo,and the residue is flash chromatogaraphed over silica gel to afford diol708.

G. Tosylate 709

To a solution of diol 708 (134 mg, 0.25 mmol) in pyridine (2 mL) isadded p-toluenesulfonyl chloride (52 mg, 0.27 mmol). After 3 hr, thereaction mixture is diluted with ether (30 mL), and washed with ice cold1M hydrochloric acid (60 mL), saturated NaHCO₃ solution (20 mL), andbrine (20 mL) and then concentrated in vacuo. The residue is purified bycolumn chromatography to give a monotosylate 709.

H. Epoxide 710

A solution of tosylate 709 (145 mg, 0.21 mmol) in methanol (3.0 mL) isadded potassium carbonate (10 mg) at room temperature. The mixture isstirred for 20 min, and then diluted with water (60 mL) and extractedwith ethyl acetate (2×20 mL). The combined organic layers are washedwith brine and concentrated in vacuo. Flash chromatography providesepoxide 710.

I. Alcohol 711

To a solution of 710 (41 mg, 79 mmol) in CH₂ Cl₂ (3.0 mL) at 0° C. isadded water (0.15 mL) and 2, 3-dichloro-5,6-dicyano-1, 4-benzoquinone(60 mg, 0.26 mmol).

The mixture is stirred at 0C for 5 hr, diluted with CH₂ Cl₂ (15 mL),dried over MgSO₄, and filtered through a column of silica gel. Followingconcentration in vacuo, the crude 711 is used without furtherpurification.

J. Carbamate 712

To a solution of 711 (8.7 mg, 22 mmol) in CH₂ Cl₂ (1.0 mL) is addedtrichloroacetyl isocyanate (0.20 mL, 1.7 mmol) at room temperature.After 30 min, the mixture is diluted with CH₂ Cl₂ (20 mL), and someneutral Al₂ O₃ (500 mg) is added. The mixture is then stirred at roomtemperature for 2 hr, then filtered though a short column of silica gel,and concentrated in vacuo. The residue is purified by flashchromatography to afford 712.

K. Hydroxy-urethane 701

A solution of 712 (6.0 mg, 14 mmol) in 48% HF-acetonitrile (1:9, 1.0 mL)is stirred at room temperature for 12 hr. The reaction is quenched bysaturated NaHCO₃ (5.0 mL). The mixture is extracted with ethyl acetate(3×10 mL).

The combined organic phase is then washed with brine (5.0 mL), driedover MgSO₄, and concentrated in vacuo. The residue is purified by flashchromatography afford 701.

EXAMPLE 58 (FIGS. 27 and 28)

A. Iodide 802

A solution of alcohol 16 (see, Smith, et al., J. Am. Chem. Soc. 1995,117, 12011) (410 mg, 0.360 mmol) in dry benzene/ether (1:2, 10 mL) istreated with triphenylphosphine (378 mg, 1.44 mmol) and imidazole (111mg, 1.62 mmol). After complete dissolution of the imidazole, iodine (301mg, 1.19 mmol) is added with vigorous stirring. The reaction mixture isstirred 2 h and then treated with triethylamine (1.7 mL). The resultantsolution is diluted with CH₂ Cl₂ (30 mL) and washed with saturatedaqueous Na₂ S₂ O₃ (40 mL), saturated aqueous NaHCO₃ (40 mL), and brine(2×40 mL). The organic phase is dried over MgSO₄, filtered andconcentrated in vacuo. Purification of the residue by flashchromatography affords iodide 802.

B. Phosphonium salt 803

To a solution of iodide 802 (410 mg, 0.325 mmol) in benzene (20 mL) isadded triphenylphosphine (1.00 g, 3.81 mmol).

The mixture is heated at 80° C. for 24 hr, cooled to room temperature,and concentrated in vacuo. The residue is washed with hexane (2×20 mL).Flash chromatography affords phosphonium salt 803.

C. Alkene 805

A solution of 803 (460 mg, 0.30 mmol) in tetrahydrofuran (9.0 mL) iscooled to -10° C. A solution of n-butyl lithium (1.0M in hexane, 0.29mL, 0.29 mmol) is added dropwise over 5 min, and the resultant solutionis stirred for 50 min at room temperature. Then the mixture is recooledto -78° C. and a solution of aldehyde 804 (39 mg, 0.3 mmol) intetrahydrofuran (1.5 mL) is added. The mixture is stirred for 10 min at-78° C., and 1 hr at 0° C. The reaction is quenched with saturatedaqueous NH₄ Cl (20 mL), the resultant mixture is extracted with ether(40 mL), and the ether layer is washed with water (30 mL) and brine (30mL), dried over MgSO₄, filtered and concentrated in vacuo. Flashchromatography of the residue affords 805.

D. Diol 806

Acetonide 805 (280 mg, 0.22 mol) is dissolved in 80% aqueous acetic acid(3.5 mL) at room temperature. The reaction mixture is stirred for 4 hrat room temperature and then diluted with water (40 mL). The mixture isextracted with ethyl acetate (2×10 mL). The combined organic layers arewashed with saturated NaHCO₃ solution, and brine (10 mL each), and thendried over MgSO₄. The organic solution is concentrated in vacuo, and theresidue is flash chromatogaraphed over silica gel to afford diol 806.

E. Tosylate 807

To a solution of diol 806 (235 mg, 0.19 mmol) in pyridine (2 mL) at 0°C. is added p-toluenesulfonyl chloride (45 mg, 0.23 mmol). After 3 hr,the reaction mixture is diluted with ether (30 mL), and washed with icecold 1M hydrochloric 30 acid (30 mL), saturated NaHCO₃ solution (20 mL),and brine (20 mL) and then concentrated in vacuo. The residue ispurified by column chromatography to give a monotosylate 807.

F. Epoxide 808

To a solution of tosylate 807 (187 mg, 0.21 mmol) in methanol (3.0 mL)is added potassium carbonate (10 mg) at room temperature. The mixture isstirred for 20 min, and then diluted with water (60 mL) and extractedwith ethyl acetate (2×20 mL). The combined organic layers were washedwith brine and concentrated in vacuo. Flash chromatography providesepoxide 808.

G. Lactone 809

To a solution of 808 (110 mg, 93 mmol) in tetrahydrofuran-acetonitrile(10 mL, 2:1) is added a phosphate buffer solution (pH=7.0, 3.5 mL), andHgCl₂ (2.3 g). The suspension is stirred at room temperature for 40 min,then diluted with ether (30 mL), washed with brine (2×30 mL), dried overMgSO₄, and concentrated in vacuo. Flash chromatography affords thelactol as an α/β anomeric mixture. This material is used directly in thenext oxidation: Under argon atmosphere, a solution of the lactols indimethylsulfoxide (3.0 mL) is treated with acetic anhydride (0.60 mL).After 2 days at room temperature, the mixture is diluted with ether (50mL), washed with saturated NaHCO₃ (30 mL), brine (30 mL), dried overMgSO₄, and concentrated in vacuo. Flash chromatography provides 809.

H. Alcohol 810

To a solution of 809 (90 mg, 79 mmol) in CH₂ Cl₂ (3.0 mL) at 0° C. isadded water (0.15 mL) and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone(60 mg, 0.26 mmol). The mixture is stirred at 0° C. for 5 hr, dilutedwith CH₂ CL₂ (15 mL), dried over MgSO₄, and filtered through a column ofsilica gel. Following concentration in vacuo, the crude 810 is used inthe next reaction without further purification.

I. Carbamate 811

To a solution of 810 (22 mg, 22 mmol) in CH₂ Cl₂ (1.0 mL) is addedtrichloroacetyl isocyanate (0.20 mL, 1.7 mmol) at room temperature.After 30 min, the mixture is diluted with CH₂ Cl₂ (20 mL), and someneutral Al₂ O₃ (500 mg) is added. The mixture is then stirred at roomtemperature for 2 hr, then filtered though a short column of silica gel,and concentrated in vacuo. Flash chromatography affords 811.

J. Epoxide analog 812

A solution of 811 (15 mg, 14 mmol) in tetrahydrofuran (1.0 mL) is cooledto 0° C., and treated with a 1.0M solution of tetrabutylammoniumfluoride in tetrahydrofuran (0.14 mL, 0.14 mmol). The reaction mixtureis stirred for 2 hr, and diluted with water (20 mL). The mixture isextracted with ethyl acetate (3×10 mL). The combined organic phase isthen washed with brine (10 mL), dried over MgSO₄, concentrated in vacuo.Flash chromatography affords 801.

EXAMPLE 59 (FIG. 29)

A. Alcohol 903

Phosphonium salt 15 (98.0 mg, 0.092 mmol) is dried azeotropically withdry benzene and heated at 50° C. under vacuum for 3 hr before use. It isthen dissolved in tetrahydrofuran (0.7 mL). Sodiumbis(trimethylsilyl)amide (1.0M in tetrahydrofuran, 86 mL, 0.0855 mmol)is added at -78° C., and the mixture is stirred for 20 min and thenrecooled to -78° C. A solution of aldehyde 902 (60 mmol) intetrahydrofuran (300 mL) is added, and the mixture is stirred for 10 minat -78° C., and 2 hr at room temperature. The reaction is quenched withsaturated aqueous NH₄ Cl (1.0 mL). The resultant mixture is extractedwith ether (30 mL), and the ether layer is washed with water (30 mL) andbrine (30 mL), dried over MgSO₄, filtered and concentrated in vacuo.Flash chromatography provides an olefin. A solution of the olefin (44mmol) in CH₂ Cl₂ is cooled to -78° C. Diisobutylaluminum hydride (1.0Min toluene, 440 mL, 0.40 mmol) is added dropwise over 5 min, and theresultant solution is stirred for 10 min at -78° C. and 30 min at 0° C.The reaction is quenched with a saturated solution of Rochelle's salt,and the mixture is diluted with ether (60 mL), washed with Rochellesolution, and brine (30 mL each), dried over MgSO₄, filtered andconcentrated in vacuo. Flash chromatography provides alcohol 903.

B. Diene 905

A solution of 903 (0.012 mmol) and Et₃ N (42 mL, 0.30 mmol) in CH₂ Cl₂(2.0 mL) is cooled to 0° C. and a solution of SO₃ -pyridine complex (40mg, 0.251 mmol) in dimethylsulfoxide (0.6 mL) is added. The mixture isstirred at 0° C. for 45 min and then diluted with ethyl acetate (30 mL),washed with aqueous NaHSO₄ (1.0M, 30 mL) and brine (2×30 mL), dried overMgSO₄, and concentrated in vacuo. Flash chromatography affords analdehyde. A solution of allyldiphenylphosphine 904 (0.19 mmol) intetrahydrofuran (1.0 mL) is cooled to -78° C. and t-butyl lithium (1.7Min pentane, 0.122 mmol) is added. The mixture is stirred at 0° C. for 30min, recooled to -78° C. and treated titanium tetra-i-propoxide (0.15mmol). After 30 min, a cold (-78° C.) solution of the aldehyde (0.26mmol) in tetrahydrofuran (1.0 mL) is introduced via cannula, and themixture is stirred 10 min further at -78° C. and at 0° C. for 1 hr.Iodomethane (0.32 mmol) is added, and the reaction is maintained at 0°C. for 30 min, warmed to room temperature, protected from light, andstirred overnight. The reaction mixture is diluted with ether (30 mL),washed with 1.0M aqueous NaHSO₄ and brine (30 mL each), dried overMgSO₄, concentrated in vacuo. Flash chromatography affords diene 905.

C. Glycoside 908

A solution of 905 (83 mmol) in methanol (2 mL) is treated withpyridinium p-toluenesulfonate (ca. 4 mg) and stirred at 40° C. for 30min. The mixture is diluted with ether (20 mL) and washed successivelywith saturated aqueous NaHCO₃ solution (25 mL) and brine (10 mL), andthen dried over MgSO₄. The organic solution is concentrated in vacuo,and the residue is passed through a column of silica gel to give analcohol.

To a solution of glycosyl bromide 906 (75 mmol) in CH₂ Cl₂ (2.0 mL) isadded HgBr₂ (7 mmol) and powdered molecular sieves (4 Å, 50 mg) andstirred for 60 min at room temperature. The mixture is then cooled to 0°C., and the alcohol (74 mmol) prepared above is added in CH₂ Cl₂ (0.7mL). The resultant mixture is stirred 6 hr at 0° C. and then warmed toroom temperature and diluted with CH₂ Cl₂ (10 mL), and filtered througha pad of celite. The filtrate is washed with aqueous KI solution, anddried over MgSO₄. The organic solution is concentrated in vacuo, and theresidue is passed through a column of silica gel to give an anomericmixture of glycosides 908.

D. Triol 901

To a solution of 908 (79 mmol) in CH₂ Cl₂ (3.0 mL) at 0° C. is addedwater (0.15 mL) and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (60 mg,0.26 mmol). The mixture is stirred at 0° C. for 5 hr, diluted with CH₂Cl₂ (15 mL), dried over MgSO₄, and filtered through a column of silicagel. Following concentration in vacuo, the crude alcohol is used fornext step without further purification. To a solution of the alcohol (22mmol) in CH₂ Cl₂ (1.0 mL) is added trichloroacetyl isocyanate (0.20 mL,1.7 mmol) at room temperature. After 30 min, the mixture is diluted withCH₂ Cl₂ (20 mL), and some neutral Al₂ O₃ (500 mg) is added. The mixtureis then stirred at room temperature for 2 hr, then filtered though ashort column of silica gel, and concentrated in vacuo. Flashchromatography affords a carbamate. A solution of the carbamate (14mmol) in 48% HF-acetonitrile (1:9, 1.0 mL) is stirred at roomtemperature for 12 hr. The reaction is quenched by saturated NaHCO₃ (5.0mL). The mixture is extracted with ethyl acetate (3×10 mL). The combinedorganic phase is then washed with brine(5.0 mL), dried over MgSO₄,concentrated in vacuo. Flash chromatography affords 901.

EXAMPLE 60 (FIG. 30)

A. Olefin 1001

A solution of model phosphonium salt (0.0917 mmol) in THF (700 mL) iscooled to -78° C. and treated with NaHMDS (1.0M in THF, 85.5 mL, 0.0855mmol). The mixture is stirred for 20 min at 0° C., recooled to -78° C.and aldehyde C (0.0570 mmol) in THF (300 mL) is added. After 10 min at-78° C. and 2 h at room temperature, the mixture is quenched withsaturated aqueous NH₄ Cl (1.0 mL) and extracted with ether (30 mL). Theether solution is washed with water, brine (30 mL each), dried overMgSO₄, filtered and concentrated. Flash chromatography provides olefin1001.

B. Lactone 1002

A solution of olefin 1001 (0.00597 mmol) in THF/CH₃ CN (2:1, 1.50 mL) istreated with pH 7.0 phosphate buffer (500 mL) and HgCl₂ (215 mg). Thesuspension is stirred at room temperature for 40 min, diluted with ether(30 mL), washed with brine (2×30 mL), dried over MgSO₄, filtered andconcentrated. Pipette flash chromatography (5% ethyl acetate/hexane)provides a mixture of lactols as a colorless oil which is furthertreated with DMSO (1.0 mL) and Ac₂ O (200 mL) at room temperature for 2days. The mixture is diluted with ether (30 mL), washed with saturatedNaHCO₃ (30 mL), brine (30 mL), dried over MgSO₄, filtered andconcentrated. Flash chromatography provides lactone 1002.

C. Model Compound 1003

A solution of olefin 1002 (5.5 mmol) in 480 HF--CH₃ CN (1:9, 1.0 mL) isstirred at room temperature for 12 h, then quenched with saturatedaqueous NaHCO₃ (5.0 mL). The mixture is extracted with ethyl acetate(3×10 mL). The combined organic extracts are washed with brine (5.0 mL),dried over MgSO₄, filtered and concentrated. Pipette flashchromatography (gradient elution, 1:30 to 1:6 MeOH/CHCl₃) provides 1003.

EXAMPLE 61 (FIGS. 31 and 32) I. General Procedure for Synthesis ofHydroxy Aldehydes 1104

A. TBS ether 1102a

A solution of bromide 1101a (see, Jacquesy, et al., Tetrahedron 1981,37, 747) (20 mmol) in ether (40 mL) is added slowly to a -78 0C solutionof tert-butyllitium (40 mmol, 1.7M in pentane). After 1 h at -78° C.,the cold solution is transferred to a suspension of copper (I) iodide(10 mmol) in ether at 0° C. After an additional 30 min at 0° C., asolution of benzyl (S)-(+)-glycidyl ether (9 mmol) in ether (20 mL) isadded and the reaction is allowed to warm to room temperature. After18-24 h, the reaction is quenched by the addition oftert-butyldimethylsilyl triflate (10 mmol). The reaction mixture ispoured into saturated aqueous sodium bicarbonate (100 mL). The aqueouslayer is separated and extracted with ether (2×50 mL). The combinedorganics are washed with saturated aqueous brine (50 mL), dried overmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 1102a.

B. Alcohol 1103a

To a solution of 1102a (6 mmol) in ethyl acetate-ethanol (8:1, 90 mL) isadded palladium on carbon (10% wet, 500 mg). The mixture is stirredunder hydrogen atmosphere for 3-6 h, then filtered and concentrated invacuo. The residue is purified by flash chromatography to afford 1103a.

C. Aldehyde 1104a

Oxalyl chloride (1.5 mmol) is added dropwise to a -78° C. solution ofdimethyl sulfoxide (3 mmol) in dichloromethane (4 mL). After 15 min, a-78° C. solution of 1103a (1 mmol) in dichloromethane (2 mL) is addedvia canula. After an additional 15 min, diisopropylethylamine (4.5 mmol)is added and the reaction is gradually warmed to room temperature over 1h and quenched with aqueous sodium bisulfate. The mixture is dilutedwith ether (50 mL) and is washed with water (2×30 mL), saturated aqueousbrine (2×30 mL), is dried over magnesium sulfate and concentrated invacuo. The residue is purified by flash chromatography to afford 1104a.

II. General Procedure for the Conversion of 1104 to Arene Analog 1111

A. Diene 1105

Phosphonium salt 15 (see, Smith, et al., J. Am. Chem. Soc. 1995, 117,12011) (0.2 mmol) is dissolved in anhydrous tetrahydrofuran (2 mL) andchilled to 0° C. A solution of sodium bis(trimethylsilyl)amide (0.2mmol, 1.0M in tetrahydrofuran) is added and the reaction mixture isstirred 30 min at 0° C. After cooling to -78° C., a solution of aldehyde1104 (0.1 mmol) in tetrahydrofuran (2 mL) is added and the mixture isstirred 10 min at -78° C. and 2 h at room temperature. Saturated aqueousammonium chloride (2 mL) is added and the resultant mixture is extractedwith ether (3×20 mL). The ethereal layer is washed with water (2×25 mL)and saturated aqueous brine (25 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by flash chromatographyto afford 1105.

B. Hydroxy diene 1106

A -78° C. solution of 1105 (0.05 mmol) in CH₂ Cl₂ (5 ML) is treated withdiisobutylaluminum hydride (0.5 mL, 1.0M in toluene). The resultantsolution is stirred 10 min at -78° C. and 30 min at 0° C. The reactionis quenched with a saturated solution of sodium potassium tartrate (50mL) and the mixture is diluted with ether (60 mL). The organic layer isseparated, dried over magnesium sulfate, and concentrated in vacuo. Theresidue is purified by flash chromatography to afford 1106.

C. Aldehyde 1107

Oxalyl chloride (1.5 mmol) is added dropwise to a -78° C. solution ofdimethyl sulfoxide (3 mmol) in dichloromethane (4 mL). After 15 min, a-78° C. solution of 1106 (1 mmol) in dichloromethane (2 mL) is added viacanula. After an additional 15 min, diisopropylethylamine (4.5 mmol) isadded and the reaction is gradually warmed to room temperature over 1 hand quenched with aqueous sodium bisulfate. The mixture is diluted withether (50 mL) and is washed with water (2×30 mL), saturated aqueousbrine (2×30 mL), is dried over magnesium sulfate and concentrated invacuo. The residue is purified by flash chromatography to afford 1107.

D. Tetraene 1108

A solution of diphenylallylphosphine (0.08 mL, 0.38 mmol) intetrahydrofuran (2 mL) is cooled to -78° C. and tert-butyllithium (0.14mL, 1.7M in pentane) is added. The mixture is warmed to 0° C. for 30min, then recooled to -78° C. and treated with titanium (IV)isopropoxide (0.30 mmol). After 30 min, aldehyde 1107 (0.30 mmol) isintroduced as a solution in tetrahydrofuran (2 mL). The resultantsolution is stirred at -78° C. for 15 min and at 0° C. for 1 h. Methyliodide (0.64 mmol) is added, and the reaction is warmed to roomtemperature for 12 h. The reaction mixture is diluted with ether (60mL), washed with aqueous sodium bisulfate (30 mL, 1.0M), saturatedaqueous brine (30 mL), and is dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by flash chromatographyto afford 1108.

E. Alcohol 1109

To a solution of 1108 (0.050 mmol) in dichloromethane (3 mL) at 0° C. isadded water (50 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.018mmol). After 1 h, the reaction mixture is diluted with ethyl acetate (50mL), washed with saturated aqueous brine (3×25 mL), dried over magnesiumsulfate and concentrated in vacuo. The residue is purified by flashchromatography to afford 1109.

F. Carbamate 1110

To a solution of 1109 (0.010 mmol) in dichloromethane (2 mL) is addedtrichloroacetyl isocyanate (1.00 mmol). After 30 min, the reactionmixture is diluted with dichloromethane (4 mL) and neutral alumina (1 g)is added. The resultant suspension is stirred an additional 4 h. Thereaction mixture is filtered and the concentrated filtrate ischromatographed on silica gel to afford 1110.

G. Arene analog 1111

A solution of 1110 (0.010 mmol) in 480 hydrofluoric acid-acetonitrile(1:9, 2 mL) is stirred at ambient temperature. After 12 h, saturatedaqueous sodium bicarbonate (25 mL) is added and the mixture is extractedwith ethyl acetate (3×20 mL). The combined organics are dried overmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 1111.

Those skilled in the art will appreciate that numerous changes andmodifications may be made to the preferred embodiments of the inventionand that such changes and modifications may be made without departingfrom the spirit of the invention. It is therefore intended that theappended claims cover all equivalent variations as fall within the truespirit and scope of the invention.

What is claimed is:
 1. A process of producing a diene of the formula:##STR36## comprising contacting a phosphonium salt of the formula##STR37## with base and an alkylthiol of the formula: ##STR38## wherein:R₁, R₂, R₃, R₆, R₇, R₈, R₁₁, R₁₂ and R₁₃ are, independently, C₁ -C₁₀alkyl;X is a halogen; Z, Z₁ and Z₂ are, O; R₄, R₉, R₁₄, and R₁₅ are,independently, acid labile hydroxyl protecting groups; R₅ is C₆ -C₁₄aryl; Y is O, S or NR'; R' and R₁₆ are, independently, hydrogen or C₁-C₆ alkyl; and R₃₈ is C₆ -C₁₄ aryl.
 2. The process of claim 1wherein:R₁, R₂, R₃, R₆, R₇, R₈, R₁₁ and R₁₂ are methyl; R₄, R₉, R₁₄ aret-butyldimethylsilyl; R₅ is p-methoxyphenyl; R₁₃ is ethyl; R₁₆ ishydrogen; and Y, Z₁ and Z₂ are O.
 3. The process of claim 1 wherein saidbase is sodium hexamethyldisilazide or n-butyllithium withhexamethylphosphoramide.
 4. A process for producing an alkene of theformula: ##STR39## comprising: (a) contacting an organometallic reagentof the formula: ##STR40## with a vinyl halide of the formula: ##STR41##or (b) contacting a vinyl halide of formula: ##STR42## with anorganometallic compound of formula: ##STR43## wherein: R₁, R₂, R₃, R₆,R₇ and R₈ are, independently, C₁ -C₁₀ alkyl;M is Li, Cu, Mg, or Zn; X isa halogen; Z₁ and Z₂ are, O; R₄ and R₉ are, independently, acid labilehydroxyl protecting groups; R₅ is C₆ -C₁₄ aryl; R' is hydrogen or C₁ -C₆alkyl; and R₁₀ is an acid stable hydroxyl protecting group.
 5. Theprocess of claim 4 wherein R₁, R₂, R₃, R₆, R₇ and R₈ are, independently,C₁ -C₄ alkyl.
 6. The process of claim 4 wherein:R₁, R₂, R₃, R₆, R₇ andR₈ are methyl; X is iodide; Z₁ and Z₂ are O; R₄ and R₉ aret-butyldimethylsilyl; R₅ is p-methoxyphenyl; and R₁₀ is p-methoxybenzyl.7. The process of claim 4 wherein M is Li.
 8. A process of producing alactone of the formula: ##STR44## comprising: (a) contacting a diene ofthe formula ##STR45## with an organometallic compound of the formula:##STR46## or (b) contacting an organometallic compound having formula:##STR47## with a vinyl halide having formula: ##STR48## wherein: R₁, R₂,R₃, R₆, R₇, R₈, R₁₁, R₁₂ and R₁₃ are, independently, C₁ -C₁₀ alkyl;M isLi, Cu, Mg, or Zn; X is a halogen; Z, Z₁ and Z₂ are, O; R₄, R₉, R₁₄, andR₁₅ are, independently, acid labile hydroxyl protecting groups; R₅ is C₆-C₁₄ aryl; R' and R₁₆ are, independently, hydrogen or C₁ -C₆ alkyl; andR₂₄ is hydrogen; and R₂₅ is hydrogen or an acid stable hydroxylprotecting group.
 9. A process of producing a diene of the formula:##STR49## comprising contacting a phosphonium salt of the formula:##STR50## with base and an alkylthiol of the formula: ##STR51## wherein:R₆, R₇, R₈, R₁₁, R₁₂ and R₁₃ are, independently, C₁ -C₁₀ alkyl;X is ahalogen; Z is O; R₉, R₁₄, and R₁₅ are, independently, acid labilehydroxyl protecting groups; Y is O, S or NR'; R' and R₁₆ are,independently, hydrogen or C₁ -C₆ alkyl; and R₁₈ is C₆ -C₁₄ aryl.